Quinoxalines derivatives and pharmaceutical compositions and kits

ABSTRACT

A variety of specific compounds within the scope of formula I 
                         
which are useful as PI3K inhibitors and can be employed for the treatment of autoimmune diseases, inflammation, cardiovascular diseases, neurodegenerative diseases and tumours, and pharmaceutical compositions and kits containing said specific compounds.

BACKGROUND OF THE INVENTION

The invention was based on the object of finding novel compounds havingvaluable properties, in particular those which can be used for thepreparation of medicaments.

The present invention relates to compounds and the use thereof for themodulation, in particular for the inhibition, of the activity orfunction of the phosphoinositide 3′-OH kinase family (hereinafter PI3kinases), advantageously PI3Kα, PI3Kδ, PI3Kβ and/or PI3Kγ.The presentinvention advantageously relates to the use of quinoxaline derivativesin the treatment of one or more disease states selected from: autoimmunedisorders, inflammatory diseases, cardiovascular diseases,neurodegenerative diseases, allergy, asthma, pancreatitis, multiorganfailure, kidney diseases, blood platelet aggregation, cancer, spermmotility, transplant rejection, graft rejection and lung injuries.

Cell membranes provide a large store of secondary messengers that can beenlisted in a variety of signal transduction pathways. As regards thefunction and regulation of effector enzymes in phospholipid signallingpathways, these enzymes generate secondary messengers from the membranephospholipid pools. Class I PI3 kinases (for example PI3Kα) aredual-specificity kinase enzymes, i.e. they exhibit both lipid kinaseactivity (phosphorylation of phosphoinositides) and protein kinaseactivity, shown to be capable of phosphorylation of protein assubstrate, including autophosphorylation as intramolecular regulatorymechanism. These enzymes of phospholipid signalling are activated byvarious extracellular signals, such as growth factors, mitogens,integrins (cell-cell interactions), hormones, cytokines, viruses, andneurotransmitters, as described in Scheme I below, and also byintracellular regulation by other signaling molecules (cross-talk, wherethe original signal can activate some parallel pathways, which in asecond step transmit signals to PI3Ks by intracellular signalingevents), such as, for example, small GTPases, kinases, or phosphatases.Intracellular regulation can also occur as a result of aberrantexpression or lack of expression of cellular oncogenes or tumoursuppressors. The intracellular inositol phospholipid (phosphoinositide)signaling pathways begin with activation of signaling molecules(extracellular ligands, stimuli, receptor dimerisation, transactivationby a heterologous receptor (for example receptor tyrosine kinase) andwith the recruitment and activation of PI3K, including the involvementof G protein-linked transmembrane receptor integrated into the plasmamembrane.

PI3K converts the membrane phospholipid PI(4.5)P₂ into PI(3,4,5)P₃,which functions as secondary messenger. PI and PI(4)P are likewisesubstrates of PI3K and can be phosphorylated and converted into PI3P andPI(3,4)P₂, respectively. In addition, these phosphoinositides can beconverted into other phosphoinositides by 5′-specific and 3′-specificphosphatases, meaning that PI3K enzyme activity results either directlyor indirectly in the generation of two 3′-phosphoinositide subtypeswhich function as secondary messengers in intracellular signaltransduction pathways (Trends Biochem. Sci. 22(7) pp. 267-72 (1997) byVanhaesebroeck et al; Chem. Rev. 101(8) pp. 2365-80 (2001) by Leslie etal (2001); Annu. Rev. Cell. Dev. Biol. 17p, 615-75 (2001) by Katso etal. and Cell. MoI. Life Sci. 59(5) pp. 761-79 (2002) by Toker et al.).Multiple PI3K isoforms categorised by their catalytic subunits, theirregulation by corresponding regulatory subunits, expression patterns andsignal-specific functions (p110α, β, δ and γ) perform this enzymereaction (Exp. Cell. Res. 25 (1) pp. 239-54 (1999) by Vanhaesebroeck andKatso et al., 2001, see above).

The closely related isoforms p110α and β are expressed ubiquitously,while δ and γ are expressed more specifically in the haematopoietic cellsystem, in the smooth muscle cells, myocytes and endothelial cells(Trends Biochem. Sci. 22(7) pp. 267-72 (1997) by Vanhaesebroeck et al.).Their expression can also be regulated in an inducible manner dependingon the cellular tissue type and stimuli as well as in accordance withthe particular disease. The inducibility of protein expression includesprotein synthesis as well as protein stabilisation, which is partlyregulated by association with regulatory subunits.

To date, eight mammalian PI3Ks have been identified, divided into 3 mainclasses (I, II and III) on the basis of sequence homology, structure,binding partners, mode of activation, and substrate preference. Invitro, class I PI3Ks are able to phosphorylate phosphatidylinositol(PI), phosphatidylinositol 4-phosphate (PI4P) and phosphatidylinositol4,5-bisphosphate (PI(4,5)P₂) to give phosphatidylinositol 3-phosphate(PI3P), phosphatidylinositol 3,4-bisphosphate (PI(3,4)P₂, andphosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P₃, respectively.Class II PI3Ks phosphorylate PI and phosphatidylinositol 4-phosphate.Class III PI3Ks can only phosphorylate PI (Vanhaesebroeck et al., 1997,see above; Vanhaesebroeck et al., 1999, see above, and Leslie et al,2001, see above).

As illustrated in Scheme I above, phosphoinositide 3-kinases (PI3Ks)phosphorylate the hydroxyl of the third carbon atom on the inositolring. The phosphorylation of phosphoinositides which converts Ptdlnsinto 3,4,5-triphosphate (PtdIns(3,4,5)P₃), PtdIns(3,4)P₂ and PtdIns(3)Pproduces secondary messengers for various signal transduction pathways,as are essential, inter alia, for cell proliferation, celldifferentiation, cell growth, cell size, cell survival, apoptosis,adhesion, cell mobility, cell migration, chemotaxis, invasion,cytoskeletal rearrangement, cell shape changes, vesicle trafficking andmetabolic pathway (Katso et al, 2001, see above, and Mol. Med. Today6(9) pp. 347-57 (2000) by Stein). G protein-coupled receptors mediatephosphoinositide 3′-OH kinase activation via small GTPases, such as Gβγand Ras, and consequently PI3K signaling plays a central role in thedevelopment and coordination of cell polarity and dynamic organisationof the cytoskeleton—which together provide the driving force for cellmovement.

Chemotaxis—the directed movement of cells in the direction of aconcentration gradient of chemical attractants, which are also calledchemokines, is also involved in many important diseases, such asinflammation/autoimmunity, neurodegeneration, angiogenesis,invasion/metastasis and wound healing (Immunol. Today 21(6) pp. 260-4(2000) by Wyman et al.; Science 287(5455) pp. 1049-53 (2000) by Hirschet al.; FASEB J. 15(11) pp. 2019-21 (2001) by Hirsch et al., and Nat.Immunol. 2(2) pp. 108-15 (2001) by Gerard et al.).

Advances using genetic approaches and pharmacological tools haveprovided insights into signalling and molecular pathways which promotechemotaxis in response to chemical attractant-activated, Gprotein-coupled sensors. PI3 kinase, which is responsible for thegeneration of these phosphorylated signalling products, was originallyidentified as an activity which is associated with viral oncoproteinsand growth factor tyrosine kinases which phosphorylatephosphatidylinositol (PI) and its phosphorylated derivatives at the3′-hydroxyl of the inositol ring (Panayotou et al., Trends Cell Biol. 2pp. 358-60 (1992)). However, more recent biochemical studies have shownthat class I PI3 kinases (for example class IB isoform PI3Kγ) aredual-specificity kinase enzymes, which means that they exhibit bothlipid kinase activity and protein kinase activity, shown to be capableof phosphorylation of other proteins as substrates, as well asautophosphorylation as an intramolecular regulatory mechanism.

PI3 kinase activation is therefore probably involved in various cellularresponses, including cell growth, differentiation and apoptosis (Parkeret al., Current Biology, 5 pp. 577-99 (1995); Yao et al., Science, 267pp. 2003-05 (1995)). PI3 kinases appear to be involved in a number ofaspects of leukocyte activation. A p85-associated PI3 kinase activityhas been shown to associate physically with the cytoplasmic domain ofCD28, which is an important co-stimulatory molecule for the activationof T cells by antigen (Pages et al., Nature, 369 pp. 327-29 (1994);Rudd, Immunity 4 pp. 527-34 (1996)). Activation of T cells by CD28lowers the threshold for activation by antigen and increases themagnitude and duration of the proliferative response. These effects areaccompanied by increases in the transcription of a number of genes, suchas, inter alia, interleukin-2 (IL2), an important T cell growth factor(Fraser et al., Science 251 pp. 313-16 (1991)). If CD28 is mutated insuch a way that it can no longer interact with PI3 kinase, initiation ofIL-2 production fails, which suggests a crucial role for PI3 kinase in Tcell activation. PI3Kγ has been identified as a promoter ofG-β-γ-dependent regulation of JNK activity, and G-β-γ are subunits ofheterotrimeric G proteins (Lopez-Ilasaca et al, J. Biol. Chem. 273(5)pp. 2505-8 (1998)). Cellular processes in which PI3Ks play an essentialrole include suppression of apoptosis, reorganisation of the actinskeleton, cardiac myocyte growth, glycogen synthase stimulation byinsulin, TNFα-promoted neutrophil priming and superoxide generation, andleukocyte migration and adhesion to endothelial cells.

Laffargue et al., Immunity 16(3) pp. 441-51 (2002), have described thatPI3Kγ relays inflammatory signals via various G(i)-coupled receptors andthat it is crucial for mast cell function, stimuli in connection withleukocytes, and immunology, including cytokines, chemokines, adenosines,antibodies, integrins, aggregation factors, growth factors, viruses orhormones (J. Cell. Sci. 114(Pt 16) pp. 2903-10 (2001) by Lawlor et al.;Laffargue et al., 2002, see above, and Curr. Opinion Cell Biol. 14(2)pp. 203-13 (2002) by Stephens et al.).

Specific inhibitors against individual members of a family of enzymesprovide invaluable tools for deciphering the functions of each enzyme.Two compounds, LY294002 and wortmannin (see below), have been widelyused as PI3 kinase inhibitors. These compounds are non-specific PI3Kinhibitors, since they do not distinguish between the four members ofclass I PI3 kinases. For example, the IC₅₀ values of wortmannin againsteach of the various class I PI3 kinases are in the range from 1 to 10nM. Correspondingly, the IC₅₀ values of LY294002 against each of thesePI3 kinases are about 15 to 20 μM (Fruman et al., Ann. Rev. Biochem.,67, pp. 481-507 (1998)), in addition it has IC₅₀ values of 5-10 μM onCK2 protein kinase and a slight inhibitory activity on phospholipases.Wortmannin is a fungal metabolite which irreversibly inhibits PI3Kactivity by bonding covalently to the catalytic domain of this enzyme.The inhibition of PI3K activity by wortmanin eliminates the subsequentcellular response to the extracellular factor. For example, neutrophilsrespond to the chemokine fMet-Leu-Phe (fMLP) by stimulation of PI3K andsynthesis of Ptdlns (3, 4, 5)P₃. This synthesis correlates withactivation of the respiratory burst which is involved in the destructionof the neutrophils of invading microorganisms. Treatment of neutrophilswith wortmannin prevents the fMLP-induced respiratory burst response(Thelen et al., Proc. Natl. Acad. Sci. USA, 91, pp. 4960-64 (1994)).Indeed, these experiments with wortmannin, as well as other experimentalevidence, show that PI3K activity in cells of haematopoietic lineage, inparticular neutrophils, monocytes and other types of leukocytes, areinvolved in many of the non-memory immune response associated with acuteand chronic inflammation.

Based on studies with wortmannin, there is evidence that PI3 kinasefunction is also necessary for some aspects of leukocyte signalling by Gprotein-coupled receptors (Thelen et al., 1994, see above). In addition,it has been shown that wortmannin and LY294002 block neutrophilmigration and superoxide release. Carboxygenase-inhibiting benzofuranderivatives are disclosed by John M. Janusz et al., in J. Med. Chem.1998; Vol. 41, No. 18.

It is now well understood that deregulation of oncogenes andtumour-suppressor genes contributes to the formation of malignanttumours, for example by increasing cell growth and proliferation orincreased cell survival. It is now also known that signalling pathwayspromoted by the PI3K family play a central role in a number of cellprocesses, such as, inter alia, in proliferation and survival, andderegulation of these pathways is a causative factor in a broad spectrumof human cancer diseases and other diseases (Katso et al., Annual Rev.Cell Dev. Biol, 2001, 17: 615-617, and Foster et al, J. Cell Science.2003, U6: 3037-3040).

Class I PI3K is a heterodimer consisting of a catalytic p110 subunit anda regulatory subunit, and the family is further divided into class Iaand class Ib enzymes on the basis of the regulatory partners and theregulation mechanisms. Class Ia enzymes consist of three differentcatalytic subunits (p110α, p110β, and p110δ), which dimerise with fivedifferent regulatory subunits (p85α, p55α, p50α, p85β and p55γ), whereall catalytic subunits are able to interact with all regulatory subunitsto form various heterodimers. Class Ia PI3Ks are generally activated inresponse to growth factor stimulation of receptor tyrosine kinases viainteraction of the regulatory SH2 domain subunit with specificphosphotyrosine residues of the activated receptor or adaptor proteins,such as IRS-1. Small GTPases (for example ras) are likewise involved inthe activation of PI3K together with receptor tyrosine kinaseactivation. Both p110α and p110β are constitutively involved in all celltypes, whereas p110δ expression is more restricted to leukocytepopulations and some epithelial cells. By contrast, the only class Ibenzyme consists of a catalytic p110γ subunit, which interacts with aregulatory p101 subunit. In addition, the class Ib enzyme is activatedby G protein-coupled receptor (GPCR) systems, and its expression appearsto be limited to leukocytes.

There is now clear evidence showing that class Ia PI3K enzymescontribute to tumorigenesis in a large number of human cancer diseases,either directly or indirectly (Vivanco and Sawyers, Nature ReviewsCancer, 2002, 2, 489-501). For example, the p110α subunit is amplifiedin some tumours, such as, for example, in ovarian tumours (Shayesteh, etal., Nature Genetics, 1999, 21: 99-102) and cervix (Ma et al, Oncogene,2000, 19: 2739-2744). Recently, activating mutations in p110α (PIK3CAgene) have been associated with various other tumours, such as, forexample, colon and breast and lung tumours (Samuels, et al., Science,2004, 304, 554). Tumour-related mutations in p85α have likewise beenidentified in cancer diseases, such as ovarian and colon cancer (Philpet al., Cancer Research, 2001, 61, 7426-7429). Besides direct effects,activation of class I PI3Ks is probably involved in tumorigenic eventsoccurring upstream of signalling pathways, for example by means ofligand-dependent or ligand-independent activation of receptor tyrosinekinases, GPCR systems or integrins (Vara et al., Cancer TreatmentReviews, 2004, 30, 193-204). Examples of such upstream signallingpathways include overexpression of the receptor tyrosine kinase Erb2 ina number of tumours which lead to activation of PI3K-promoted pathways(Harari et al., Oncogene, 2000, Jj), 6102-6114) and overexpression ofthe oncogene Ras (Kauffmann-Zeh et al., Nature, 1997, 385, 544-548). Inaddition, class Ia PI3Ks may contribute indirectly to tumorigenesiscaused by various downstream signalling events. For example, the loss offunction of the PTEN tumour-suppressor phosphatase which catalyses theconversion of PI(3,4,5,)P₃ back to PI(4,5)P₂ is associated with a verybroad range of tumours via deregulation of the PI3K-promoted productionof PI(3,4,5)P₃ (Simpson and Parsons, Exp. Cell Res., 2001, 264, 29-41).In addition, the increase in the effects of other PI3K-promotedsignalling events probably contributes to a number of cancer diseases,for example by activation of AKT (Nicholson and Andeson, CellularSignaling, 2002, 14, 381-395).

Besides a role in the promotion of proliferative and survival signallingin tumour cells, there is good evidence that class I PI3K enzymes alsocontribute to tumorigenesis via their function in tumour-associatedstromal cells. PI3K signalling is known to play an important role in thepromotion of angiogenic events in endothelial cells in response topro-angiogenic factors, such as VEGF (abid et al., Arterioscler. Thromb.Vasc. Biol., 2004, 24, 294-300). Since class I PI3K enzymes are alsoinvolved in mobility and migration (Sawyer, Expert Opinion investing.Drugs, 2004, 13, 1-19), PI3K inhibitors are thought to provide atherapeutic benefit via inhibition of tumour cell invasion andmetastasis.

The synthesis of small compounds which specifically inhibit, regulateand/or modulate PI3 kinase signal transduction is therefore desirableand an aim of the present invention.

It has been found that the compounds according to the invention andsalts thereof have very valuable pharmacological properties while beingwell tolerated.

It has been found that the compounds according to the invention areinhibitors of the phosphoinositide 3-kinases (PI3Ks).

If the phosphoinositide 3-kinase (PI3K) enzyme is inhibited by acompound according to the invention, PI3K is unable to exert itsenzymatic, biological and/or pharmacological effects. The compoundsaccording to the invention are therefore suitable for the treatment ofautoimmune diseases, inflammatory diseases, cardiovascular diseases,neurodegenerative diseases, allergy, asthma, pancreatitis, multiorganfailure, kidney diseases, blood platelet aggregation, cancer, spermmotility, transplant rejection, graft rejection and lung injuries.

The compounds of the formula (I) are suitable, in particular, asmedicaments for the treatment of autoimmune diseases, inflammatorydiseases, cardiovascular diseases, neurodegenerative diseases, allergy,asthma, pancreatitis, multiorgan failure, kidney diseases, bloodplatelet aggregation, cancer, sperm motility, transplant rejection,graft rejection and lung injuries.

According to an embodiment of the present invention, the compounds ofthe formula (I) are inhibitors of one or more phosphatoinositide3-kinases (PI3Ks), advantageously phosphatoinositide 3-kinase γ (PI3Kγ),phosphatoinositide 3-kinase α (PI3Kα), phosphatoinositide 3-kinase β(PI3Kβ), and/or phosphatoinositide 3-kinase δ (PI3Kδ).

The compounds of the formula (I) are suitable for the modulation, inparticular for the inhibition, of the activity of phosphatoinositide3-kinases (PI3Ks), advantageously phosphatoinositide 3-kinase (PI3Kα).The compounds according to the invention are therefore also suitable forthe treatment of disorders which are promoted by PI3Ks. The treatmentincludes the modulation—in particular the inhibition ordownregulation—of phosphatoinositide 3-kinases.

The compounds according to the invention are preferably used for thepreparation of a medicament for the treatment of a disorder selectedfrom multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupuserythematosus, inflammatory bowel disease, lung inflammation, thrombosisor brain infection or inflammation, such as meningitis or encephalitis,Alzheimer's disease, Huntington's disease, CNS trauma, stroke orischaemic states, cardiovascular diseases, such as atherosclerosis,cardiac hypertrophy, cardiac myocyte dysfunction, hypertension orvasoconstriction.

The compounds of the formula (I) are preferably suitable for thetreatment of autoimmune diseases or inflammatory diseases, such asmultiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupuserythematosus, inflammatory bowel disease, lung inflammation, thrombosisor brain infection or inflammation, such as meningitis or encephalitis.

The compounds of the formula (I) are preferably suitable for thetreatment of neurodegenerative diseases, such as, inter alia, multiplesclerosis, Alzheimer's disease, Huntington's disease, CNS trauma, strokeor ischaemic states.

The compounds of the formula (I) are preferably suitable for thetreatment of cardiovascular diseases, such as atherosclerosis, cardiachypertrophy, cardiac myocyte dysfunction, hypertension orvasoconstriction.

The compounds of the formula (I) are preferably suitable for thetreatment of chronic obstructive pulmonary disease, anaphylactic shockfibrosis, psoriasis, allergic diseases, asthma, stroke, ischaemicstates, ischemia-reperfusion, blood platelet aggregation or activation,skeletal muscle atrophy or hypertrophy, leukocyte recruitment in cancertissue, angiogenesis, invasion metastasis, in particular melanoma,Karposi's sarcoma, acute and chronic bacterial and viral infections,sepsis, transplant rejection, graft rejection, glomerulosclerosis,glomerulonephritis, progressive renal fibrosis, endothelial andepithelial injuries in the lung, and lung airway inflammation.

Since the pharmaceutically active compounds of the present invention areactive as PI3 kinase inhibitors, in particular the compounds whichinhibit pI3Kα, either selectively or together with one or more of PI3Kδ,PI3Kβ and/or PI3Kγ, they have therapeutic utility in the treatment ofcancer.

The invention preferably relates to a method for the treatment of cancerin a mammal, including humans, where the cancer is selected from: brain(gliomas), glioblastomas, leukaemias, Bannayan-Zonana syndrome, Cowdendisease, Lhermitte-Duclos disease, breast cancer, inflammatory breastcancer, Wilm's tumour, Ewing's sarcoma, rhabdomyosarcoma, ependymoma,medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma,ovary, pancreas, prostate, sarcoma, osteosarcoma, giant-cell tumour ofbone and thyroid.

The invention preferably relates to a method for the treatment of cancerin a mammal, including humans, where the cancer is selected from:lymphoblastic T-cell leukaemia, chronic myelogenous leukaemia, chroniclymphocytic leukaemia, hairy-cell leukaemia, acute lymphoblasticleukaemia, acute myelogenous leukaemia, chronic neutrophilic leukaemia,acute lymphoblastic T-cell leukaemia, plasmacytoma, immunoblastic largecell leukaemia, mantle cell leukaemia, multiple myeloma,megakaryoblastic leukaemia, multiple myeloma, acute megakaryocyticleukaemia, promyelocytic leukaemia and erythroleukaemia.

The invention preferably relates to a method for the treatment of cancerin a mammal, including humans, where the cancer is selected frommalignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma,lymphoblastic T-cell lymphoma, Burkitt's lymphoma and follicularlymphoma.

The invention preferably relates to a method for the treatment of cancerin a mammal, including humans, where the cancer is selected from:neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulvarcancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma,oesophageal cancer, salivary gland cancer, hepatocellular cancer, bowelcancer, nasopharyngeal cancer, buccal cancer, mouth cancer, GIST(gastrointestinal stromal tumour) and testicular cancer.

The compounds of the formula I can furthermore be used for the isolationand investigation of the activity or expression of PI3 kinase. Inaddition, they are particularly suitable for use in diagnostic methodsfor diseases in connection with unregulated or disturbed PI3 kinaseactivity.

It can be shown that the compounds according to the invention have anantiproliferative action in vivo in a xenotransplant tumour model. Thecompounds according to the invention are administered to a patienthaving a hyperproliferative disease, for example to inhibit tumourgrowth, to reduce inflammation associated with a lymphoproliferativedisease, to inhibit transplant rejection or neurological damage due totissue repair, etc. The present compounds are suitable for prophylacticor therapeutic purposes. As used herein, the term “treatment” is used torefer to both prevention of diseases and treatment of preexistingconditions. The prevention of proliferation is achieved byadministration of the compounds according to the invention prior to thedevelopment of overt disease, for example to prevent the growth oftumours, prevent metastatic growth, diminish restenosis associated withcardiovascular surgery, etc. Alternatively, the compounds are used forthe treatment of ongoing diseases by stabilising or improving theclinical symptoms of the patient.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be determined by in vitro tests.Typically, a culture of the cell is combined with a compound accordingto the invention at various concentrations for a period of time which issufficient to allow the active agents to induce cell death or to inhibitmigration, usually between about one hour and one week. In vitro testingcan be carried out using cultivated cells from a biopsy sample. Theviable cells remaining after the treatment are then counted.

The dose varies depending on the specific compound used, the specificdisease, the patient status, etc. A therapeutic dose is typicallysufficient considerably to reduce the undesired cell population in thetarget tissue while the viability of the patient is maintained. Thetreatment is generally continued until a considerable reduction hasoccurred, for example an at least about 50% reduction in the cellburden, and may be continued until essentially no more undesired cellsare detected in the body.

For identification of a signal transduction pathway and for detection ofinteractions between various signal transduction pathways, variousscientists have developed suitable models or model systems, for examplecell culture models (for example Khwaja et al., EMBO, 1997, 16, 2783-93)and models of transgenic animals (for example White et al., Oncogene,2001, 20, 7064-7072). For the determination of certain stages in thesignal transduction cascade, interacting compounds can be utilised inorder to modulate the signal (for example Stephens et al., BiochemicalJ., 2000, 351, 95-105). The compounds according to the invention canalso be used as reagents for testing kinase-dependent signaltransduction pathways in animals and/or cell culture models or in theclinical diseases mentioned in this application.

Measurement of the kinase activity is a technique which is well known tothe person skilled in the art. Generic test systems for thedetermination of the kinase activity using substrates, for examplehistone (for example Alessi et al., FEBS Lett. 1996, 399, 3, pages333-338) or the basic myelin protein, are described in the literature(for example Campos-González, R. and Glenney, Jr., J. R. 1992, J. Biol.Chem. 267, page 14535).

For the identification of kinase inhibitors, various assay systems areavailable. In scintillation proximity assay (Sorg et al., J. ofBiomolecular Screening, 2002, 7, 11-19) and flashplate assay, theradioactive phosphorylation of a protein or peptide as substrate withγATP is measured. In the presence of an inhibitory compound, a decreasedradioactive signal, or none at all, is detectable. Furthermore,homogeneous time-resolved fluorescence resonance energy transfer(HTR-FRET) and fluorescence polarisation (FP) technologies are suitableas assay methods (Sills et al., J. of Biomolecular Screening, 2002,191-214).

Other non-radioactive ELISA assay methods use specificphospho-antibodies (phospho-ABs). The phospho-AB binds only thephosphorylated substrate. This binding can be detected bychemiluminescence using a second peroxidase-conjugated anti-sheepantibody (Ross et al., 2002, Biochem. J.).

PRIOR ART

Pyrazine derivatives and the use thereof as PI3K inhibitors aredisclosed in WO 2007/023186 A1.

Pyridopyrimidines are described as PI3 kinase inhibitors in WO2009/039140 A1. Other quinoxaline derivatives are disclosed as PI3Kinhibitors in WO 2008/127594. Still other quinoxaline derivatives aredescribed in WO 2008/101979 A1 for the treatment of autoimmune diseases,inflammation or cancer. Compared with other quinoxaline derivativesdisclosed in WO 2008/101979, the compounds according to the inventionhave improved inhibiting properties on PI3 kinase (Table 1).

Other quinoxaline derivatives for combating cancer are disclosed in WO2008/021389 A2.

Further quinoxaline derivatives for combating cancer are disclosed in WO2007/044729 A2.

SUMMARY OF THE INVENTION

The invention relates to compounds of the formula I

-   in which-   R denotes H, Hal or A,-   R¹ denotes Het¹, Ar¹, A, (CH₂)_(n)NH₂, (CH₂)_(n)NHA, (CH₂)_(n)NA₂,    (CH₂)_(p)CN or (CH₂)_(p)SO₂A,-   R² denotes Ar² or Het²,-   Het¹ denotes a mono- or bicyclic saturated, unsaturated or aromatic    heterocycle having 1 to 4 N, O and/or S atoms, which may be    unsubstituted or mono-, di- or trisubstituted by A, (CH₂)_(n)NH₂,    (CH₂)_(n)NHA, (CH₂)_(n)NA₂, CF₂NH₂, CF₂NHA, CF₂NA₂, (CH₂)_(n)CONH₂,    (CH₂)_(n)CONHA, (CH₂)_(n)CONA₂, CN, ═O, Hal, (CH₂)_(n)OH,    (CH₂)_(n)OA, COOH, COOA, 0(CH₂)_(n)OH, O(CH₂)_(n)OA, O(CH₂)_(n)NH₂,    NH(CH₂)_(n)NH₂, SO₂A and/or SO₂NH₂,-   Ar¹ denotes phenyl, naphthyl or biphenyl, each of which is    unsubstituted or mono-, di- or trisubstituted by CN, (CH₂)_(n)CONH₂,    (CH₂)_(n)CONHA, (CH₂)_(n)CONA₂, (CH₂)_(n)OH, (CH₂)_(n)OA,    (CH₂)_(n)NH₂, (CH₂)_(n)NHA, (CH₂)_(n)NA₂, NHCOOA, NHCOA, Hal, COOH,    COOA, COHet³, A, NHSO₂A, SO₂NH₂, SO₂NHA, SO₂NA₂ and/or SO₂A,-   Ar² denotes

-   A′ denotes unbranched or branched alkyl having 1-4 C atoms,    -   in which 1-5H atoms may be replaced by F,-   Het² denotes a mono- or bicyclic unsaturated or aromatic heterocycle    having 1 to 4 N, O and/or S atoms, which is substituted by OCH₃ and    may additionally be substituted by R⁴,-   R³ denotes Hal, (CH₂)_(n)Het³, O(CH₂)_(n)Het³ or unbranched or    branched alkyl having 1-10 C atoms, in which 1-7H atoms may be    replaced by OH, F, Cl and/or Br, and/or in which one, two or three    non-adjacent CH₂ groups may be replaced by O, NH, NA', S, SO, SO₂    and/or CH═CH groups,-   R⁴ denotes (CH₂)_(n)CONH₂, (CH₂)_(n)CONHA, (CH₂)_(n)CONA₂ or    unbranched or branched alkyl having 1-10 C atoms, in which 1-7H    atoms may be replaced by OH, F, Cl and/or Br, and/or in which one,    two or three non-adjacent CH₂ groups may be replaced by O, NH, NA',    S, SO, SO₂ and/or CH═CH groups,-   Het³ denotes a monocyclic saturated heterocycle having 1 to 4 N, O    and/or S atoms, which may be unsubstituted or mono- or disubstituted    by A, Hal and/or ═O,-   A denotes unbranched or branched alkyl having 1-10 C atoms,    -   in which 1-7H atoms may be replaced by F and/or Cl,    -   or    -   cyclic alkyl having 3-7 C atoms,-   Hal denotes F, Cl, Br or I,-   p denotes 1, 2, 3, 4, 5 or 6,-   n denotes 0, 1, 2, 3 or 4,-   and pharmaceutically usable salts, tautomers and stereoisomers    thereof, including mixtures thereof in all ratios,

Compounds of the formula I are also taken to mean the hydrates andsolvates of these compounds, furthermore pharmaceutically usablederivatives.

The invention also relates to the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andthe hydrates and solvates of these compounds. solvates of the compoundsare taken to mean adductions of inert solvent molecules onto thecompounds which form owing to their mutual attractive force. Solvateare, for example, mono- or dihydrates or alcoholates.

Pharmaceutically usable derivatives are taken to mean, for example, thesalts of the compounds according to the invention and also so-calledprodrug compounds. Prodrug derivatives are taken to mean compounds ofthe formula I which have been modified by means of, for example, alkylor acyl groups, sugars or oligopeptides and which are rapidly cleaved inthe organism to form the effective compounds according to the invention.

These also include biodegradable polymer derivatives of the compoundsaccording to the invention, as described, for example, in Int. J. Pharm.115, 61-67 (1995).

The expression “effective amount” denotes the amount of a medicament orof a pharmaceutical active compound which causes in a tissue, system,animal or human a biological or medical response which is sought ordesired, for example, by a researcher or physician.

In addition, the expression “therapeutically effective amount” denotesan amount which, compared with a corresponding subject who has notreceived this amount, has the following consequence:

improved treatment, healing, prevention or elimination of a disease,syndrome, condition, complaint, disorder or side effects or also thereduction in the advance of a disease, complaint or disorder.

The term “therapeutically effective amount” also encompasses the amountswhich are effective for increasing normal physiological function.

The invention also relates to the use of mixtures of the compounds ofthe formula I, for example mixtures of two diastereomers, for example inthe ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.

These are particularly preferably mixtures of stereoisomeric compounds.

The invention relates to the compounds of the formula I and saltsthereof and to a process for the preparation of compounds of the formulaI and pharmaceutically usable salts, tautomers and stereoisomersthereof, characterised in that a compound of the formula II

-   in which-   R and R¹ have the meanings indicated in claim 1,-   and L denotes Cl, Br, I or a free or reactively functionally    modified OH group,-   is reacted with a compound of the formula III    H₂N—R²  III,-   in which-   R² has the meaning indicated in claim 1,-   and/or-   a base or acid of the formula I is converted into one of its salts.

Above and below, the radicals R, R¹ and R² have the meanings indicatedin the case of the formula I, unless expressly indicated otherwise.

-   Abbreviations:-   DCM=dichloromethane-   DMA=dimethylacetamide-   DMF=dimethylformamide-   EA=ethyl acetate-   PE=petroleum ether-   RT=room temperature-   TFA=trifluoroacetic acid

A denotes alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4,5, 6, 7, 8, 9 or 10 C atoms. A preferably denotes methyl, furthermoreethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl,furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl,1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, further preferably, for example, trifluoromethyl.A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 Catoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethylor 1,1,1-trifluoroethyl.

Cyclic alkyl (cycloalkyl) preferably denotes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl.

A′ denotes alkyl, is unbranched (linear) or branched, and has 1, 2, 3 or4 C atoms.

R preferably denotes H.

Ar¹ denotes, for example, phenyl, o-, m- or p-tolyl, o-, m- orp-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl,o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- orp-aminophenyl, o-, m- or p-(N-methylamino)phenyl, o-, m- orp-(N-methylaminocarbonyl)phenyl, o-, m- or p-acetamidophenyl, o-, m- orp-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- orp-ethoxycarbonylphenyl, o-, m- or p-(N,N-dimethylamino)phenyl, o-, m- orp-(N,N-dimethylaminocarbonyl)phenyl, o-, m- or p-(N-ethylamino)phenyl,o-, m- or p-(N,N-diethylamino)phenyl, o-, m- or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- orp-(methylsulfonamido)phenyl, o-, m- or p-(methylsulfonyl)phenyl, o-, m-or p-methylsulfanylphenyl, o-, m- or p-cyanophenyl, o-, m- orp-carboxyphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- orp-aminosulfonylphenyl, furthermore preferably 2,3-, 2,4-, 2,5-, 2,6-,3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl,2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl,3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro-,2-amino-4-chloro-, 2-amino-5-chloro- or 2-amino-6-chlorophenyl,2-nitro-4-N,N-dimethylamino- or 3-nitro-4-N,N-dimethylaminophenyl,2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl,2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl,3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl,3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Het¹ denotes, irrespective of further substitutions, for example 2- or3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2,4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, indazolyl, 1-, 2-, 4-or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-,6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, T- or 8-quinolyl, 1-, 3-,4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-,4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-,7- or 8-2H-benzo-1,4-oxazinyl, further preferably 1,3-benzodioxol-5-yl,1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl,2,1,3-benzoxadiazol-5-yl or dibenzofuranyl.

The heterocyclic radicals may also be partially or fully hydrogenated.

Irrespective of further substitutions, Het¹ can thus also denote, forexample, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4-or 5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2-or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl,2,5-dihydro-1-, -2-, -3-, 4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl,tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or-5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-,-3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or-6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl,tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or-5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or-5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-,-3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-,-4-, -5-, -6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2H-benzo-1,4-oxazinyl, further preferably2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)phenyl or also3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl,3,4-dihydro-2-oxo-1H-quinazolinyl, 2,3-dihydrobenzoxazolyl,2-oxo-2,3-dihydrobenzoxazolyl, 2,3-dihydrobenzimidazolyl,1,3-dihydroindole, 2-oxo-1,3-dihydroindole or2-oxo-2,3-dihydrobenzimidazolyl.

Het¹ particularly preferably denotes piperidinyl, pyrrolidinyl,morpholinyl, piperazinyl, oxazolidinyl, tetrahydrothienyl,thiomorpholinyl, pyrazolyl, pyridinyl, pyrimidinyl, furyl, thienyl,thiazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, isoxazolyl orimidazolidinyl, where the radicals may also be mono-, di- ortrisubstituted by A, (CH₂)_(n)NH₂, (CH₂)_(n)NHA, (CH₂)_(n)NA₂, CF₂NH₂,CF₂NHA, CF₂NA₂, (CH₂)_(n)CONH₂, (CH₂)_(n)CONHA, (CH₂)_(n)CONA₂, CNand/or ═O.

Het² denotes, irrespective of further substitutions, for example 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, indazolyl, 1-, 2-, 4-or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-,6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-,4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-,4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-,7- or 8-2H-benzo-1,4-oxazinyl, further preferably 1,3-benzodioxol-5-yl,1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl,2,1,3-benzoxadiazol-5-yl or dibenzofuranyl.

The heterocyclic radicals may also be partially hydrogenated.

Irrespective of further substitutions, Het² can thus also denote, forexample, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2h-benzo-1,4-oxazinyl, further preferably2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)phenyl or also3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl,3,4-dihydro-2-oxo-1H-quinazolinyl, 2,3-dihydrobenzoxazolyl,2-oxo-2,3-dihydrobenzoxazolyl, 2,3-dihydrobenzimidazolyl,1,3-dihydroindole, 2-oxo-1,3-dihydroindole or2-oxo-2,3-dihydrobenzimidazolyl.

Het² preferably denotes

-   where-   X denotes O, NH or S,-   R⁴ denotes H, (CH₂)_(n)CONH₂, (CH₂)_(n)CONHA, (CH₂)_(n)CONA₂ or    unbranched or branched alkyl having 1-10 C atoms, in which 1-7H    atoms may be replaced by OH, F, Cl and/or Br, and/or in which one,    two or three non-adjacent CH₂ groups may be replaced by O, NH, NA′,    S, SO, SO₂ and/or CH═CH groups.

Het² particularly preferably denotes benzodioxolyl, dihydrobenzofuranyl,dihydrobenzodioxinyl or benzofuranyl, where the radicals aremonosubstituted by OCH₃ and may additionally be substituted by R⁴.

R³ preferably denotes Hal, (CH₂)_(n)Het³, O(CH₂)_(n)Het³, A′, OA′,(CH₂)_(n)NH₂, (CH₂)_(n)NHA′, (CH₂)_(n)NA′₂, (CH₂)_(n)OH, (CH₂)_(n)OA′,O(CH₂)_(n)CHA′OH, O(CH₂)_(n)CHA′OA′, O(CH₂)_(n)CHA′(CH₂)_(n)OH,O(CH₂)_(n)CHA′(CH₂)_(n)OA′, O(CH₂)_(m)SO₂A′, O(CH₂)_(m)SOA′,O(CH₂)_(m)O(CH₂)_(m)OH, O(CH₂)_(m)O(CH₂)_(m)OA′,O(CH₂)_(n)CHOH(CH₂)_(n)OH, O(CH₂)_(n)SO(CH₂)_(n)OH,O(CH₂)_(n)SO₂(CH₂)_(n)OH, O(CH₂)_(m)NA(CH₂)_(m)OH, O(CH₂)_(m)OH,O(CH₂)_(m)OA′, NH(CH₂)_(m)OH, NH(CH₂)_(n)NH₂ or NH(CH₂)_(m)OA′, where

-   m denotes 1, 2, 3 or 4.

R⁴ preferably denotes (CH₂)_(n)CONH₂, (CH₂)_(n)CONHA′, (CH₂)_(n)CONA′₂,A′, OA′, (CH₂)_(n)NH₂, (CH₂)_(n)NHA′, (CH₂)_(n)NA′₂, (CH₂)_(n)OH,(CH₂)_(n)OA′, O(CH₂)_(n)CHA′OH, O(CH₂)_(n)CHA′OA′,O(CH₂)_(n)CHA′(CH₂)_(n)OH, O(CH₂)_(n)CHA′(CH₂)_(n)OA′, O(CH₂)_(m)SO₂A′,O(CH₂)_(m)SOA′, O(CH₂)_(m)O(CH₂)_(m)OH, O(CH₂)_(m)O(CH₂)_(m)OA′,O(CH₂)_(n)CHOH(CH₂)_(n)OH, O(CH₂)_(n)SO(CH₂)_(n)OH,O(CH₂)_(n)SO₂(CH₂)_(n)OH, O(CH₂)_(m)NA(CH₂)_(m)OH, O(CH₂)_(m)OH,O(CH₂)_(m)OA′, NH(CH₂)_(m)OH, NH(CH₂)_(n)NH₂ or NH(CH₂)_(m)OA′, where

-   m denotes 1, 2, 3 or 4.

Het³ preferably denotes piperidinyl, pyrrolidinyl, acetidinyl,morpholinyl, piperazinyl, oxazolidinyl, tetrahydrothienyl,tetrahydropyranyl or thiomorpholinyl, where the radicals may also bemono- or disubstituted by ═O, Hal and/or A′.

D denotes, irrespective of further substitutions, for examplethiazolediyl, thiophenediyl, furandiyl, pyrrolediyl, oxazolediyl,isoxazolediyl, oxadiazolediyl, pyrazolediyl, imidazolediyl,thiadiazolediyl, pyridazinediyl, pyrazinediyl, pyridinediyl orpyrimidinediyl, where the radicals may also be mono-, di- ortrisubstituted by Hal and/or A.

Hal preferably denotes F, Cl or Br, but also I, particularly preferablyF or Cl.

Throughout the invention, all radicals which occur more than once may beidentical or different, i.e. are independent of one another.

The compounds of the formula I may have one or more chiral centres andcan therefore occur in various stereoisomeric forms. The formula Iencompasses all these forms.

Accordingly, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundsmay be expressed by the following sub-formulae Ia to Ih, which conformto the formula I and in which the radicals not designated in greaterdetail have the meaning indicated for the formula I, but in which

-   in Ia R denotes H;-   in Ib Het¹ denotes piperidinyl, pyrrolidinyl, morpholinyl,    piperazinyl, oxazolidinyl, tetrahydrothienyl, thiomorpholinyl,    pyrazolyl, pyridinyl, pyrimidinyl, furyl, thienyl, thiazolyl,    oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, isoxazolyl or    imidazolidinyl, where the radicals may also be mono-, di- or    trisubstituted by A, (CH₂)_(n)NH₂, (CH₂)_(n)NHA, (CH₂)_(n)NA₂,    CF₂NH₂, CF₂NHA, CF₂NA₂, (CH₂)_(n)CONH₂, (CH₂)_(n)CONHA,    (CH₂)_(n)CONA₂, CN and/or ═O;-   in Ic Het² denotes

-   X denotes O, NH or S,-   R⁴ denotes H, (CH₂)_(n)CONH₂, (CH₂)_(n)CONHA, (CH₂)_(n)CONA₂ or    unbranched or branched alkyl having 1-10 C atoms, in which 1-7H    atoms may be replaced by OH, F, Cl and/or Br, and/or in which one,    two or three non-adjacent CH₂ groups may be replaced by O, NH, NA′,    S, SO, SO₂ and/or CH═CH groups;-   in Id Het² denotes benzodioxolyl, dihydrobenzofuranyl,    dihydrobenzodioxinyl or benzofuranyl, where the radicals are    monosubstituted by OCH₃ and may additionally be substituted by R⁴;-   in Ie R³ denotes Hal, (CH₂)_(n)Het³, O(CH₂)_(n)Het³, A′, OA′,    (CH₂)_(n)NH₂, (CH₂)_(n)NHA′, (CH₂)_(n)NA′₂, (CH₂)_(n)OH,    (CH₂)_(n)OA′, O(CH₂)_(n)CHA′OH, O(CH₂)_(n)CHA′OA′,    O(CH₂)_(n)CHA′(CH₂)_(n)OH, O(CH₂)_(n)CHA′(CH₂)_(n)OA′,    O(CH₂)_(m)SO₂A′, O(CH₂)_(m)SOA′, O(CH₂)_(m)O(CH₂)_(m)OH,    O(CH₂)_(m)O(CH₂)_(m)OA′, O(CH₂)_(n)CHOH(CH₂)_(n)OH,    O(CH₂)_(n)SO(CH₂)_(n)OH, O(CH₂)_(n)SO₂(CH₂)_(n)OH,    O(CH₂)_(m)NA(CH₂)_(m)OH, O(CH₂)_(m)OH, O(CH₂)_(m)OA′, NH(CH₂)_(m)OH,    NH(CH₂)_(n)NH₂ or NH(CH₂)_(m)OA′,-   m denotes 1, 2, 3 or 4;-   in If R⁴ denotes (CH₂)_(n)CONH₂, (CH₂)_(n)CONHA′, (CH₂)_(n)CONA′₂,    A′, OA′, (CH₂)_(n)NH₂, (CH₂)_(n)NHA′, (CH₂)_(n)NA′₂, (CH₂)_(n)OH,    (CH₂)_(n)OA′, O(CH₂)_(n)CHA′OH, O(CH₂)_(n)CHA′OA′,    O(CH₂)_(n)CHA′(CH₂)_(n)OH, O(CH₂)_(n)CHA′(CH₂)_(n)OA′,    O(CH₂)_(m)SO₂A′, O(CH₂)_(m)SOA′, O(CH₂)_(m)O(CH₂)_(m)OH,    O(CH₂)_(m)O(CH₂)_(m)OA′, O(CH₂)_(n)CHOH(CH₂)_(n)OH,    O(CH₂)_(n)SO(CH₂)_(n)OH, O(CH₂)_(n)SO₂(CH₂)_(n)OH,    O(CH₂)_(m)NA(CH₂)_(m)OH, O(CH₂)_(m)OH, O(CH₂)_(m)OA′, NH(CH₂)_(m)OH,    NH(CH₂)_(n)NH₂ or NH(CH₂)_(m)OA′,-   m denotes 1, 2, 3 or 4;-   in Ig Het³ denotes piperidinyl, pyrrolidinyl, acetidinyl,    morpholinyl, piperazinyl, oxazolidinyl, tetrahydrothienyl,    tetrahydropyranyl or thiomorpholinyl, where the radicals may also be    mono- or disubstituted by ═O, Hal and/or A′;-   in Ih R denotes H,-   R¹ denotes Het¹, Ar¹, A, (CH₂)_(n)NH₂, (CH₂)_(n)NHA, (CH₂)_(n)NA₂,    (CH₂)_(p)CN or (CH₂)_(p)SO₂A,-   R² denotes Ar² or Het²,-   Het¹ denotes piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl,    oxazolidinyl, tetrahydrothienyl, thiomorpholinyl, pyrazolyl,    pyridinyl, pyrimidinyl, furyl, thienyl, thiazolyl, oxazolyl,    oxadiazolyl, imidazolyl, pyrrolyl, isoxazolyl or imidazolidinyl,    where the radicals may also be mono-, di- or trisubstituted by A,    (CH₂)_(n)NH₂, (CH₂)_(n)NHA, (CH₂)_(n)NA₂, CF₂NH₂, CF₂NHA, CF₂NA₂,    (CH₂)_(n)CONH₂, (CH₂)_(n)CONHA, (CH₂)_(n)CONA₂, CN and/or ═O,-   Ar¹ denotes phenyl, naphthyl or biphenyl, each of which is    unsubstituted or mono-, di- or trisubstituted by CN, (CH₂)_(n)CONH₂,    (CH₂)_(n)CONHA, (CH₂)_(n)CONA₂, (CH₂)_(n)OH, (CH₂)_(n)OA,    (CH₂)_(n)NH₂, (CH₂)_(n)NHA, (CH₂)_(n)NA₂, NHCOOA, NHCOA, Hal, COOH,    COOA, COHet³, A, NHSO₂A, SO₂NH₂, SO₂NHA, SO₂NA₂ and/or SO₂A,-   Ar² denotes

-   A′ denotes unbranched or branched alkyl having 1-4 C atoms, in which    1-5H atoms may be replaced by F,-   Het² denotes

-   X denotes O, NH or S,-   R³ denotes Hal, (CH₂)_(n)Het³, O(CH₂)_(n)Het³ or    -   unbranched or branched alkyl having 1-10 C atoms, in which 1-7H        atoms may be replaced by OH, F, Cl and/or Br, and/or in which        one, two or three non-adjacent CH₂ groups may be replaced by O,        NH, NA′, S, SO, SO₂ and/or CH═CH groups,-   R⁴ denotes H, (CH₂)_(n)CONH₂, (CH₂)_(n)CONHA, (CH₂)_(n)CONA₂ or    unbranched or branched alkyl having 1-10 C atoms, in which 1-7H    atoms may be replaced by OH, F, Cl and/or Br, and/or in which one,    two or three non-adjacent CH₂ groups may be replaced by O, NH, NA′,    S, SO, SO₂ and/or CH═CH groups,-   Het³ denotes piperidinyl, pyrrolidinyl, acetidinyl, morpholinyl,    piperazinyl, oxazolidinyl, tetrahydrothienyl, tetrahydropyranyl or    thiomorpholinyl, where the radicals may also be mono- or    disubstituted by ═O, Hal and/or A′,-   A denotes unbranched or branched alkyl having 1-10 C atoms,    -   in which 1-7H atoms may be replaced by F and/or Cl,    -   or    -   cyclic alkyl having 3-7 C atoms,-   Hal denotes F, Cl, Br or I,-   p denotes 1, 2, 3, 4, 5 or 6,-   n denotes 0, 1, 2, 3 or 4;-   and pharmaceutically usable salts, tautomers and stereoisomers    thereof, including mixtures thereof in all ratios.

The compounds of the formula I and also the starting materials for theirpreparation are, in addition, prepared by methods known per se, asdescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants known per se which are notmentioned here in greater detail.

Compounds of the formula I can preferably be obtained by reacting acompound of the formula II with a compound of the formula III.

The starting compounds of the formulae II and III are generally known.If they are novel, however, they can be prepared by methods known perse.

In the compounds of the formula II, L preferably denotes OH, Cl, Br, Ior a free or reactively modified OH group, such as, for example, anactivated ester, an imidazolide or alkylsulfonyloxy having 1-6 C atoms(preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) orarylsulfonyloxy having 6-10 C atoms (preferably phenyl- orp-tolylsulfonyloxy).

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −30° and180°, normally between 30° and 160°, in particular between about 40° andabout 120°.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

Particular preference is given to propanol, ethanol, butanol, ethyleneglycol, dioxane, THF or dimethoxyethane.

Pharmaceutical Salts and Other Forms

The said compounds according to the invention can be used in their finalnon-salt form. On the other hand, the present invention also encompassesthe use of these compounds in the form of their pharmaceuticallyacceptable salts, which can be derived from various organic andinorganic acids and bases by procedures known in the art.Pharmaceutically acceptable salt forms of the compounds of the formula Iare for the most part prepared by conventional methods. If the compoundof the formula I contains a carboxyl group, one of its suitable saltscan be formed by reacting the compound with a suitable base to give thecorresponding base-addition salt. Such bases are, for example, alkalimetal hydroxides, including potassium hydroxide, sodium hydroxide andlithium hydroxide; alkaline earth metal hydroxides, such as bariumhydroxide and calcium hydroxide; alkali metal alkoxides, for examplepotassium ethoxide and sodium propoxide; and various organic bases, suchas piperidine, diethanolamine and N-methylglutamine. The aluminium saltsof the compounds of the formula I are likewise included. In the case ofcertain compounds of the formula I, acid-addition salts can be formed bytreating these compounds with pharmaceutically acceptable organic andinorganic acids, for example hydrogen halides, such as hydrogenchloride, hydrogen bromide or hydrogen iodide, other mineral acids andcorresponding salts thereof, such as sulfate, nitrate or phosphate andthe like, and alkyl- and monoarylsulfonates, such as ethanesulfonate,toluenesulfonate and benzenesulfonate, and other organic acids andcorresponding salts thereof, such as acetate, trifluoroacetate,tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbateand the like. Accordingly, pharmaceutically acceptable acid-additionsalts of the compounds of the formula I include the following: acetate,adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate(besylate), bisulfate, bisulfite, bromide, butyrate, camphorate,camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate,cyclopentanepropionate, digluconate, dihydrogenphosphate,dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate(from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate,glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate,hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate,lactobionate, malate, maleate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate, phthalate, but this does not represent a restriction.

Furthermore, the base salts of the compounds according to the inventioninclude aluminium, ammonium, calcium, copper, iron(III), iron(II),lithium, magnesium, manganese(III), manganese(II), potassium, sodium andzinc salts, but this is not intended to represent a restriction. Of theabove-mentioned salts, preference is given to ammonium; the alkali metalsalts sodium and potassium, and the alkaline earth metal salts calciumand magnesium. Salts of the compounds of the formula I which are derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary and tertiary amines, substituted amines, alsoincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchanger resins, for example arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris(hydroxymethyl)methylamine(tromethamine), but this is not intended to represent a restriction.

Compounds of the present invention which contain basicnitrogen-containing groups can be quaternised using agents such as(C₁-C₄)alkyl halides, for example methyl, ethyl, isopropyl andtert-butyl chloride, bromide and iodide; di(C₁-C₄)alkyl sulfates, forexample dimethyl, diethyl and diamyl sulfate; (C₁₀-C₁₈)alkyl halides,for example decyl, dodecyl, lauryl, myristyl and stearyl chloride,bromide and iodide; and aryl(C₁-C₄)alkyl halides, for example benzylchloride and phenethyl bromide. Both water- and oil-soluble compoundsaccording to the invention can be prepared using such salts.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tromethamine, but this is not intended to represent arestriction.

Particular preference is given to hydrochloride, dihydrochloride,hydrobromide, maleate, mesylate, phosphate, sulfate and succinate.

The acid-addition salts of basic compounds of the formula I are preparedby bringing the free base form into contact with a sufficient amount ofthe desired acid, causing the formation of the salt in a conventionalmanner. The free base can be regenerated by bringing the salt form intocontact with a base and isolating the free base in a conventionalmanner. The free base forms differ in a certain respect from thecorresponding salt forms thereof with respect to certain physicalproperties, such as solubility in polar solvents; for the purposes ofthe invention, however, the salts otherwise correspond to the respectivefree base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of the formula I are formed with metals or amines, such asalkali metals and alkaline earth metals or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base-addition salts of acidic compounds according to the inventionare prepared by bringing the free acid form into contact with asufficient amount of the desired base, causing the formation of the saltin a conventional manner. The free acid can be regenerated by bringingthe salt form into contact with an acid and isolating the free acid in aconventional manner. The free acid forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free acid forms thereof.

If a compound according to the invention contains more than one groupwhich is capable of forming pharmaceutically acceptable salts of thistype, the invention also encompasses multiple salts. Typical multiplesalt forms include, for example, bitartrate, diacetate, difumarate,dimeglumine, diphosphate, disodium and trihydrochloride, but this is notintended to represent a restriction.

With regard to that stated above, it can be seen that the expression“pharmaceutically acceptable salt” in the present connection is taken tomean an active compound which comprises a compound of the formula I inthe form of one of its salts, in particular if this salt form impartsimproved pharmacokinetic properties on the active compound compared withthe free form of the active compound or any other salt form of theactive compound used earlier. The pharmaceutically acceptable salt formof the active compound can also provide this active compound for thefirst time with a desired pharmacokinetic property which it did not haveearlier and can even have a positive influence on the pharmacodynamicsof this active compound with respect to its therapeutic efficacy in thebody.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically usable salts andstereoisomers thereof, including mixtures thereof in all ratios, andoptionally excipients and/or adjuvants.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active compound perdosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g,preferably 1 mg to 700 mg, particularly preferably mg to 100 mg, of acompound according to the invention, depending on the condition treated,the method of administration and the age, weight and condition of thepatient, or pharmaceutical formulations can be administered in the formof dosage units which comprise a predetermined amount of active compoundper dosage unit. Preferred dosage unit formulations are those whichcomprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active compound. Furthermore,pharmaceutical formulations of this type can be prepared using a processwhich is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active compound with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of atablet or capsule, the active-ingredient component can be combined withan oral, non-toxic and pharmaceutically acceptable inert excipient, suchas, for example, ethanol, glycerol, water and the like. Powders areprepared by comminuting the compound to a suitable fine size and mixingit with a pharmaceutical excipient comminuted in a similar manner, suchas, for example, an edible carbohydrate, such as, for example, starch ormannitol. A flavour, preservative, dispersant and dye may likewise bepresent.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form, can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, may likewise be added in order to improve theavailability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like. The tablets are formulated by, forexample, preparing a powder mixture, granulating or dry-pressing themixture, adding a lubricant and a disintegrant and pressing the entiremixture to give tablets. A powder mixture is prepared by mixing thecompound comminuted in a suitable manner with a diluent or a base, asdescribed above, and optionally with a binder, such as, for example,carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, adissolution retardant, such as, for example, paraffin, an absorptionaccelerator, such as, for example, a quaternary salt, and/or anabsorbent, such as, for example, bentonite, kaolin or dicalciumphosphate. The powder mixture can be granulated by wetting it with abinder, such as, for example, syrup, starch paste, acadia mucilage orsolutions of cellulose or polymer materials and pressing it through asieve. As an alternative to granulation, the powder mixture can be runthrough a tabletting machine, giving lumps of non-uniform shape, whichare broken up to form granules. The granules can be lubricated byaddition of stearic acid, a stearate salt, talc or mineral oil in orderto prevent sticking to the tablet casting moulds. The lubricated mixtureis then pressed to give tablets. The compounds according to theinvention can also be combined with a free-flowing inert excipient andthen pressed directly to give tablets without carrying out thegranulation or dry-pressing steps. A transparent or opaque protectivelayer consisting of a shellac sealing layer, a layer of sugar or polymermaterial and a gloss layer of wax may be present. Dyes can be added tothese coatings in order to be able to differentiate between differentdosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can beprepared in the form of dosage units so that a given quantity comprisesa pre-specified amount of the compound. Syrups can be prepared bydissolving the compound in an aqueous solution with a suitable flavour,while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersion of the compound in anon-toxic vehicle. Solubilisers and emulsifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, beencapsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

The compounds of the formula I and salts thereof can also beadministered in the form of liposome delivery systems, such as, forexample, small unilamellar vesicles, large unilamellar vesicles andmultilamellar vesicles. Liposomes can be formed from variousphospholipids, such as, for example, cholesterol, stearylamine orphosphatidylcholines.

The compounds of the formula I and the salts thereof can also bedelivered using monoclonal antibodies as individual carriers to whichthe compound molecules are coupled. The compounds can also be coupled tosoluble polymers as targeted medicament carriers. Such polymers mayencompass polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenolor polyethylene oxide polylysine, substituted by palmitoyl radicals. Thecompounds may furthermore be coupled to a class of biodegradablepolymers which are suitable for achieving controlled release of amedicament, for example polylactic acid, poly-epsilon-caprolactone,polyhydroxybutyric acid, polyorthoesters, polyacetals,polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active compoundcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activecompound can be employed either with a paraffinic or a water-misciblecream base. Alternatively, the active compound can be formulated to givea cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active compound is dissolved orsuspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can beadministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range 20-500 microns, which isadministered in the manner in which snuff is taken, i.e. by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationencompass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multidose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilised) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary. Injectionsolutions and suspensions prepared in accordance with the recipe can beprepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours.

A therapeutically effective amount of a compound of the formula Idepends on a number of factors, including, for example, the age andweight of the animal, the precise condition that requires treatment, andits severity, the nature of the formulation and the method ofadministration, and is ultimately determined by the treating doctor orvet. However, an effective amount of a compound according to theinvention for the treatment of neoplastic growth, for example colon orbreast carcinoma, is generally in the range from 0.1 to 100 mg/kg ofbody weight of the recipient (mammal) per day and particularly typicallyin the range from 1 to 10 mg/kg of body weight per day. Thus, the actualamount per day for an adult mammal weighing 70 kg is usually between 70and 700 mg, where this amount can be administered as a single dose perday or usually in a series of part-doses (such as, for example, two,three, four, five or six) per day, so that the total daily dose is thesame. An effective amount of a salt or solvate or of a physiologicallyfunctional derivative thereof can be determined as the fraction of theeffective amount of the compound according to the invention per se. Itcan be assumed that similar doses are suitable for the treatment ofother conditions mentioned above.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically usable salts andstereoisomers thereof, including mixtures thereof in all ratios, and atleast one further medicament active compound.

The invention also relates to a set (kit) consisting of separate packsof

-   (a) an effective amount of a compound of the formula I and/or    pharmaceutically usable salts and stereoisomers thereof, including    mixtures thereof in all ratios,    -   and-   (b) an effective amount of a further medicament active compound.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules.

The set may, for example, comprise separate ampoules, each containing aneffective amount of a compound of the formula I and/or pharmaceuticallyusable salts and stereoisomers thereof, including mixtures thereof inall ratios, and an effective amount of a further medicament activecompound in dissolved or lyophilised form.

Use

The present compounds are suitable as pharmaceutical active compoundsfor mammals, especially for humans, in the treatment of diseases.

The present invention encompasses the compounds of the formula I for usein the treatment or prevention of autoimmune diseases, inflammatorydiseases, cardiovascular diseases, neurodegenerative diseases, allergy,asthma, pancreatitis, multiorgan failure, kidney diseases, bloodplatelet aggregation, cancer, sperm motility, transplant rejection,graft rejection and lung injuries.

The present invention encompasses the use of the compounds of theformula I and/or physiologically acceptable salts thereof for thepreparation of a medicament for the treatment or prevention ofautoimmune diseases, inflammatory diseases, cardiovascular diseases,neurodegenerative diseases, allergy, asthma, pancreatitis, multiorganfailure, kidney diseases, blood platelet aggregation, cancer, spermmotility, transplant rejection, graft rejection and lung injuries.

The compounds according to the invention are preferably used for thepreparation of a medicament for the treatment of a disorder selectedfrom multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupuserythematosus, inflammatory bowel disease, lung inflammation, thrombosisor brain infection or inflammation, such as meningitis or encephalitis,Alzheimer's disease, Huntington's disease, CNS trauma, stroke, orischaemic states, cardiovascular diseases, such as atherosclerosis,cardiac hypertrophy, cardiac myocyte dysfunction, hypertension orvasoconstriction.

The present invention encompasses the use of the compounds of theformula I and/or physiologically acceptable salts thereof for thepreparation of a medicament for the treatment or prevention ofautoimmune diseases or inflammatory diseases, such as multiplesclerosis, psoriasis, rheumatoid arthritis, systemic lupuserythematosus, inflammatory bowel disease, lung inflammation, thrombosisor brain infection or inflammation, such as meningitis or encephalitis.

The present invention encompasses the use of the compounds of theformula I and/or physiologically acceptable salts thereof for thepreparation of a medicament for the treatment or prevention ofneurodegenerative diseases, such as, inter alia, multiple sclerosis,Alzheimer's disease, Huntington's disease, CNS trauma, stroke orischaemic states.

The present invention encompasses the use of the compounds of theformula I and/or physiologically acceptable salts thereof for thepreparation of a medicament for the treatment or prevention ofcardiovascular diseases, such as atherosclerosis, cardiac hypertrophy,cardiac myocyte dysfunction, hypertension or vasoconstriction.

The present invention encompasses the use of the compounds of theformula I and/or physiologically acceptable salts thereof for thepreparation of a medicament for the treatment or prevention of chronicobstructive pulmonary disease, anaphylactic shock fibrosis, psoriasis,allergic diseases, asthma, stroke, ischaemic states,ischemia-reperfusion, blood platelet aggregation or activation, skeletalmuscle atrophy or hypertrophy, leukocyte recruitment in cancer tissue,angiogenesis, invasion metastasis, in particular melanoma, Karposi'ssarcoma, acute and chronic bacterial and viral infections, sepsis,transplant rejection, graft rejection, glomerulosclerosis,glomerulonephritis, progressive renal fibrosis, endothelial andepithelial injuries in the lung, and lung airway inflammation.

The present invention encompasses the use of the compounds of theformula I and/or physiologically acceptable salts thereof for thepreparation of a medicament for the treatment or prevention of cancer ina mammal, including humans, where the cancer is selected from: brain(gliomas), glioblastomas, leukaemias, Bannayan-Zonana syndrome, Cowdendisease, Lhermitte-Duclos disease, breast cancer, inflammatory breastcancer, Wilm's tumour, Ewing's sarcoma, rhabdomyosarcoma, ependymoma,medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma,ovary, pancreas, prostate, sarcoma, osteosarcoma, giant-cell tumour ofbone and thyroid.

The present invention encompasses the use of the compounds of theformula I and/or physiologically acceptable salts thereof for thepreparation of a medicament for the treatment or prevention of cancer ina mammal, including humans, where the cancer is selected from:lymphoblastic T-cell leukaemia, chronic myelogenous leukaemia, chroniclymphocytic leukaemia, hairy-cell leukaemia, acute lymphoblasticleukaemia, acute myelogenous leukaemia, chronic neutrophilic leukaemia,acute lymphoblastic T-cell leukaemia, plasmacytoma, immunoblastic largecell leukaemia, mantle cell leukaemia, multiple myeloma,megakaryoblastic leukaemia, multiple myeloma, acute megakaryocyticleukaemia, promyelocytic leukaemia and erythroleukaemia.

The present invention encompasses the use of the compounds of theformula I and/or physiologically acceptable salts thereof for thepreparation of a medicament for the treatment or prevention of cancer ina mammal, including humans, where the cancer is selected from malignantlymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblasticT-cell lymphoma, Burkitt's lymphoma and follicular lymphoma.

The invention preferably relates to a method for the treatment of cancerin a mammal, including humans, where the cancer is selected from:neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulvarcancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma,oesophageal cancer, salivary gland cancer, hepatocellular cancer, bowelcancer, nasopharyngeal cancer, buccal cancer, mouth cancer, GIST(gastrointestinal stromal tumour) and testicular cancer.

The compounds of the formula I can furthermore be used in order toprovide additive or synergistic effects in certain existing cancerchemotherapies, and/or can be used in order to restore the efficacy ofcertain existing cancer chemotherapies and radiotherapies.

Also encompassed is the use of the compounds of the formula I and/orphysiologically acceptable salts thereof for the preparation of amedicament in a mammal, where a therapeutically effective amount of acompound according to the invention is administered. The therapeuticamount varies according to the specific disease and can be determined bythe person skilled in the art without undue effort.

The disclosed compounds of the formula I can be administered incombination with other known therapeutic agents, including anticanceragents. As used here, the term “anticancer agent” relates to any agentwhich is administered to a patient with cancer for the purposes oftreating the cancer.

The anti-cancer treatment defined herein may be applied as a soletherapy or may involve, in addition to the compound of the invention,conventional surgery or radiotherapy or chemotherapy. Such chemotherapymay include one or more of the following categories of anti-tumouragents:

-   (i) antiproliferative/antineoplastic/DNA-damaging agents and    combinations thereof, as used in medical oncology, such as    alkylating agents (for example cis-platin, carboplatin,    cyclophosphamide, nitrogen mustard, melphalan, chloroambucil,    busulphan and nitrosoureas); antimetabolites (for example    antifolates such as fluoropyrimidines like 5-fluorouracil and    tegafur, raltitrexed, methotrexate, cytosine arabinoside,    hydroxyurea and gemcitabine); antitumour antibiotics (for example    anthracyclines, like adriamycin, bleomycin, doxorubicin, daunomycin,    epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin);    antimitotic agents (for example vincan alkaloids, like vincristine,    vinblastine, vindesine and vinorelbine, and taxoids, like taxol and    taxotere); topoisomerase inhibitors (for example    epipodophyllotoxins, like etoposide and teniposide, amsacrine,    topotecan, irinotecan and camptothecin) and cell-differentiating    agents (for example all-trans-retinoic acid, 13-cis-retinoic acid    and fenretinide);-   (ii) cytostatic agents, such as antioestrogens (for example    tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene),    oestrogen receptor downregulators (for example fulvestrant),    antiandrogens (for example bicalutamide, flutamide, nilutamide and    cyproterone acetate), LHRH antagonists or LHRH agonists (for example    goserelin, leuprorelin and buserelin), progesterones (for example    megestrol acetate), aromatase inhibitors (for example as    anastrozole, letrozole, vorazole and exemestane) and inhibitors of    5α-reductase, such as finasteride;-   (iii) agents which inhibit cancer cell invasion (for example    metalloproteinase inhibitors, like marimastat, and inhibitors of    urokinase plasminogen activator receptor function);-   (iv) inhibitors of growth factor function, for example such    inhibitors include growth factor antibodies, growth factor receptor    antibodies (for example the anti-erbb2 antibody trastuzumab    [Herceptin™] and the anti-erbb1 antibody cetuximab [C225]), farnesyl    transferase inhibitors, tyrosine kinase inhibitors and    serine/threonine kinase inhibitors, for example inhibitors of the    epidermal growth factor family (for example EGFR family tyrosine    kinase inhibitors, such as    N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)    quinazolin-4-amine (gefitinib, AZD1839),    N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine    (erlotinib, OSI-774) and    6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine    (CI 1033)), for example inhibitors of the platelet-derived growth    factor family and for example inhibitors of the hepatocyte growth    factor family;-   (v) antiangiogenic agents, such as those which inhibit the effects    of vascular endothelial growth factor, (for example the    anti-vascular endothelial cell growth factor antibody bevacizumab    [Avastin™], compounds such as those disclosed in published    international patent applications WO 97/22596, WO 97/30035, WO    97/32856 and WO 98/13354) and compounds that work by other    mechanisms (for example linomide, inhibitors of integrin αvβ3    function and angiostatin);-   (vi) vessel-damaging agents, such as combretastatin A4 and compounds    disclosed in international patent applications WO 99/02166, WO    00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;-   (vii) antisense therapies, for example those which are directed to    the targets listed above, such as ISIS 2503, an anti-Ras antisense;-   (viii) gene therapy approaches, including, for example, approaches    for replacement of aberrant genes, such as aberrant p53 or aberrant    BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy)    approaches, such as those using cytosine deaminase, thymidine kinase    or a bacterial nitroreductase enzyme, and approaches for increasing    patient tolerance to chemotherapy or radiotherapy, such as    multi-drug resistance gene therapy; and-   (ix) immunotherapy approaches, including, for example, ex-vivo and    in-vivo approaches for increasing the immunogenicity of patient    tumour cells, such as transfection with cytokines, such as    interleukin 2, interleukin 4 or granulocyte-macrophage colony    stimulating factor, approaches for decreasing T-cell anergy,    approaches using transfected immune cells, such as    cytokine-transfected dendritic cells, approaches using    cytokine-transfected tumour cell lines, and approaches using    anti-idiotypic antibodies.

The medicaments from Table 1 below are preferably, but not exclusively,combined with the compounds of the formula I.

TABLE 1 Alkylating agents Cyclophosphamide Lomustine BusulfanProcarbazine Ifosfamide Altretamine Melphalan Estramustine phosphateHexamethylmelamine Mechloroethamine Thiotepa Streptozocin ChlorambucilTemozolomide Dacarbazine Semustine Carmustine Platinum agents CisplatinCarboplatin Oxaliplatin ZD-0473 (AnorMED) Spiroplatin Lobaplatin(Aetema) Carboxyphthalatoplatinum Satraplatin (Johnson Matthey)Tetraplatin BBR-3464 (Hoffrnann-La Ormiplatin Roche) Iproplatin SM-11355(Sumitomo) AP-5280 (Access) Antimetabolites Azacytidine TomudexGemcitabine Trimetrexate Capecitabine Deoxycoformycin 5-fluorouracilFludarabine Floxuridine Pentostatin 2-chlorodesoxyadenosine Raltitrexed6-Mercaptopurine Hydroxyurea 6-Thioguanine Decitabine (SuperGen)Cytarabine Clofarabine (Bioenvision) 2-fluorodesoxycytidine Irofulven(MGI Pharrna) Methotrexate DMDC (Hoffmann-La Roche) IdatrexateEthynylcytidine (Taiho) Topoisomerase Amsacrine Rubitecan (SuperGen)inhibitors Epirubicin Exatecan mesylate (Daiichi) Etoposide Quinamed(ChemGenex) Teniposide or mitoxantrone Gimatecan (Sigma- Tau) Irinotecan(CPT-11) Diflomotecan (Beaufour- 7-ethyl-10- Ipsen) hydroxycamptothecinTAS-103 (Taiho) Topotecan Elsamitrucin (Spectrum) Dexrazoxanet(TopoTarget) J-107088 (Merck & Co) Pixantrone (Novuspharrna) BNP-1350(BioNumerik) Rebeccamycin analogue CKD-602 (Chong Kun Dang) (Exelixis)KW-2170 (Kyowa Hakko) BBR-3576 (Novuspharrna) Antitumour antibioticDactinomycin (Actinomycin D) Amonafide Doxorubicin (Adriamycin)Azonafide Deoxyrubicin Anthrapyrazole Valrubicin OxantrazoleDaunorubicin (Daunomycin) Losoxantrone Epirubicin Bleomycin sulfate(Blenoxan) Therarubicin Bleomycinic acid Idarubicin Bleomycin ARubidazon Bleomycin B Plicamycinp Mitomycin C Porfiromycin MEN-10755(Menarini) Cyanomorpholinodoxorubicin GPX-100 (Gem Mitoxantron(Novantron) Pharmaceuticals) Antimitotic agents Paclitaxel SB 408075(GlaxoSmithKline) Docetaxel E7010 (Abbott) Colchicine PG-TXL (CellTherapeutics) Vinblastine IDN 5109 (Bayer) Vincristine A 105972 (Abbott)Vinorelbine A 204197 (Abbott) Vindesine LU 223651 (BASF) Dolastatin 10(NCI) D 24851 (ASTA Medica) Rhizoxin (Fujisawa) ER-86526 (Eisai)Mivobulin (Warner-Lambert) Combretastatin A4 (BMS) Cemadotin (BASF)Isohomohalichondrin-B RPR 109881A (Aventis) (PharmaMar) TXD 258(Aventis) ZD 6126 (AstraZeneca) Epothilone B (Novartis) PEG-Paclitaxel(Enzon) T 900607 (Tularik) AZ10992 (Asahi) T 138067 (Tularik) !DN-5109(Indena) Cryptophycin 52 (Eli Lilly) AVLB (Prescient Vinflunine (Fabre)NeuroPharma) Auristatin PE (Teikoku Azaepothilon B (BMS) Hormone) BNP-7787 (BioNumerik) BMS 247550 (BMS) CA-4-prodrug (OXiGENE) BMS 184476(BMS) Dolastatin-10 (NrH) BMS 188797 (BMS) CA-4 (OXiGENE) Taxoprexin(Protarga) Aromatase inhibitors Aminoglutethimide Exemestan LetrozoleAtamestan (BioMedicines) Anastrazole YM-511 (Yamanouchi) FormestanThymidylate Pemetrexed (Eli Lilly) Nolatrexed (Eximias) synthaseinhibitors ZD-9331 (BTG) CoFactor ™ (BioKeys) DNA antagonistsTrabectedin (PharmaMar) Mafosfamide (Baxter Glufosfamide (BaxterInternational) International) Apaziquone (Spectrum Albumin + 32P(Isotope Pharmaceuticals) Solutions) O6-benzylguanine (Paligent)Thymectacin (NewBiotics) Edotreotid (Novartis) Farnesyl transferaseArglabin (NuOncology Labs) Tipifarnib (Johnson & inhibitors Ionafarnib(Schering-Plough) Johnson) BAY-43-9006 (Bayer) Perillyl alcohol (DORBioPharma) Pump inhibitors CBT-1 (CBA Pharma) Zosuquidartrihydrochloride Tariquidar (Xenova) (Eli Lilly) MS-209 (Schering AG)Biricodar dicitrate (Vertex) Histone acetyl- Tacedinaline (Pfizer)Pivaloyloxymethyl butyrate transferase inhibitors SAHA (Aton Pharma)(Titan) MS-275 (Schering AG) Depsipeptide (Fujisawa) MetalloproteinaseNeovastat (Aeterna CMT -3 (CollaGenex) inhibitors Laboratories)BMS-275291 (Celltech) Ribonucleoside Marimastat (British Biotech)Tezacitabine (Aventis) reductase Gallium maltolate (Titan) Didox(Molecules for Health) inhibitors Triapin (Vion) TNF-alpha Virulizin(Lorus Therapeutics) Revimid (Celgene) agonists/antagonists CDC-394(Celgene) Endothelin-A Atrasentan (Abbot) YM-598 (Yamanouchi) receptorantagonists ZD-4054 (AstraZeneca) Retinoic acid receptor Fenretinide(Johnson & Alitretinoin (Ligand) agonists Johnson) LGD-1550 (Ligand)Immunomodulators Interferon Dexosome therapy (Anosys) Oncophage(Antigenics) Pentrix (Australian Cancer GMK (Progenics) Technology)Adenocarcinoma vaccine JSF-154 (Tragen) (Biomira) Cancer vaccine(Intercell) CTP-37 (AVI BioPharma) Norelin (Biostar) JRX-2 (Immuno-Rx)BLP-25 (Biomira) PEP-005 (Peplin Biotech) MGV (Progenics) Synchrovaxvaccines !3-Alethin (Dovetail) (CTL Immuno) CLL-Thera (Vasogen) Melanomavaccine (CTL Immuno) p21-RAS vaccine (GemVa Hormonal and OestrogensPrednisone antihormonal agents Conjugated oestrogens MethylprednisoloneEthynyloestradiol Prednisolone chlorotrianisene AminoglutethimideIdenestrol Leuprolide Hydroxyprogesterone caproate GoserelinMedroxyprogesterone Leuporelin Testosterone Bicalutamide Testosteronepropionate Flutamide Fluoxymesterone Octreotide MethyltestosteroneNilutamide Diethylstilbestrol Mitotan Megestrol P-04 (Novogen) Tamoxifen2-Methoxyoestradiol Toremofin (EntreMed) Dexamethasone Arzoxifen (EliLilly) Photodynamic Talaporfin (Light Sciences) Pd-Bacteriopheophorbidagents Theralux (Theratechnologies) (Yeda) Motexafin-GadoliniumLutetium-Texaphyrin (Pharmacyclics) (Pharmacyclics) Hypericin Tyrosinekinase Imatinib (Novartis) Kahalide F (PharmaMar) inhibitorsLeflunomide(Sugen/ CEP- 701 (Cephalon) Pharmacia) CEP-751 (Cephalon)ZDI839 (AstraZeneca) MLN518 (Millenium) Erlotinib (Oncogene Science)PKC412 (Novartis) Canertjnib (Pfizer) Phenoxodiol O Squalamine (Genaera)Trastuzumab (Genentech) SU5416 (Pharmacia) C225 (ImClone) SU6668(Pharmacia) rhu-Mab (Genentech) ZD4190 (AstraZeneca) MDX-H210 (Medarex)ZD6474 (AstraZeneca) 2C4 (Genentech) Vatalanib (Novartis) MDX-447(Medarex) PKI166 (Novartis) ABX-EGF (Abgenix) GW2016 (GlaxoSmithKline)IMC-1C11 (ImClone) EKB-509 (Wyeth) EKB-569 (Wyeth) Various agentsSR-27897 (CCK-A inhibitor, BCX-1777 (PNP inhibitor, Sanofi-Synthelabo)BioCryst) Tocladesine (cyclic AMP Ranpirnase (ribonuclease agonist,Ribapharm) stimulant, Alfacell) Alvocidib (CDK inhibitor, Galarubicin(RNA synthesis Aventis) inhibitor, Dong-A) CV-247 (COX-2 Inhibitor, IvyTirapazamine Medical) (reducing agent, SRI P54 (COX-2 inhibitor,International) Phytopharm) N-Acetylcysta CapCell ™ (CYP450 (reducingagent, Zambon) stimulant, Bavarian Nordic) R-Flurbiprofen (NF-kappaBGCS-IOO (gal3 antagonist, inhibitor, Encore) GlycoGenesys) 3CPA(NF-kappaB inhibitor, G17DT immunogen (gastrin Active Biotech)inhibitor, Aphton) Seocalcitol (vitamin D Efaproxiral (oxygenator, AlloSreceptor agonist, Leo) Therapeutics) 131-I-TM-601 (DNA PI-88 (heparanaseinhibitor, antagonist, Progen) TransMolecular) Tesmilifen (histamineEflornithin (ODC inhibitor, antagonist, YM BioSciences ILEX Oncology)Histamine (histamine H2 Minodronic acid (osteoclast receptor agonist,Maxim) inhibitor, Yamanouchi) Tiazofurin (IMPDH inhibitor, Indisulam(p53 stimulant, Ribapharm) Eisai) Cilengitide (integrin antagonist,Aplidin (PPT inhibitor, Merck KGaA) PharmaMar) SR-31747 (IL-1antagonist, Rituximab (CD20 antibody, Sanofi-Synthelabo) Genentech)CCI-779 (mTOR kinase Gemtuzumab (CD33 inhibitor, Wyeth) antibody, WyethAyerst) Exisulind (PDE-V inhibitor, PG2 (haematopoiesis Cell Pathways)promoter, Pharmagenesis) CP-461 (PDE-V inhibitor, Cell Immunol ™(triclosan Pathways) mouthwash, Endo) AG-2037 (GART inhibitor,Triacetyluridine (uridine prodrug Pfizer) Wellstat) WX-UK1 SN-4071(sarcoma agent, (plasminogen activator Signature BioScience) inhibitor,Wilex) TransMID-107 ™ PBI-1402 (PMN stimulant, (immunotoxin, KSBiomedix) ProMetic LifeSciences) PCK-3145 (apoptosis Bortezomib(proteasome promoter, Procyon) inhibitor, Millennium) Doranidazole(apoptosis SRL-172 (T-cell stimulant, promoter, Pola) SR Pharma) CHS-828(cytotoxic TLK-286 (glutathione-S agent, Leo) transferase inhibitor,Telik) trans-Retinic acid PT-100 (growth factor (differentiator, NIH)agonist, Point Therapeutics) MX6 (apoptosis promoter, Midostaurin (PKCinhibitor, MAXIA) Novartis) Apomine (apoptosis promoter, Bryostatin-1(PKC stimulant, ILEX Oncology) GPC Biotech) Urocidin (apoptosispromoter, CDA-II (apoptosis promoter, Bioniche) Everlife) Ro-31-7453(apoptosis SDX-101 (apoptosis promoter, promoter, La Roche) Salmedix)Brostallicin (apoptosis Ceflatonin (apoptosis promoter, Pharmacia)promoter, ChemGenex) Alkylating agents Cyclophosphamide LomustineBusulfan Procarbazine Ifosfamide Altretamine Melphalan Estramustinephosphate Hexamethylmelamine Mechloroethamine Thiotepa StreptozocinChlorambucil Temozolomide Dacarbazine Semustine Carmustine Platinumagents Cisplatin Carboplatin Oxaliplatin ZD-0473 (AnorMED) SpiroplatinLobaplatin (Aetema) Carboxyphthalatoplatinum Satraplatin (JohnsonMatthey) Tetraplatin BBR-3464 (Hoffrnann-La Ormiplatin Roche) IproplatinSM-11355 (Sumitomo) AP-5280 (Access) Antimetabolites Azacytidine TomudexGemcitabine Trimetrexate Capecitabine Deoxycoformycin 5-fluorouracilFludarabine Floxuridine Pentostatin 2-chlorodesoxyadenosine Raltitrexed6-Mercaptopurine Hydroxyurea 6-Thioguanine Decitabine (SuperGen)Cytarabine Clofarabine (Bioenvision) 2-fluorodesoxycytidine Irofulven(MGI Pharrna) Methotrexate DMDC (Hoffmann-La Roche) IdatrexateEthynylcytidine (Taiho) Topoisomerase Amsacrine Rubitecan (SuperGen)inhibitors Epirubicin Exatecan mesylate (Daiichi) Etoposide Quinamed(ChemGenex) Teniposide or mitoxantrone Gimatecan (Sigma- Tau) Irinotecan(CPT-11) Diflomotecan (Beaufour- 7-ethyl-10- Ipsen) hydroxycamptothecinTAS-103 (Taiho) Topotecan Elsamitrucin (Spectrum) Dexrazoxanet(TopoTarget) J-107088 (Merck & Co) Pixantrone (Novuspharrna) BNP-1350(BioNumerik) Rebeccamycin analogue CKD-602 (Chong Kun Dang) (Exelixis)KW-2170 (Kyowa Hakko) BBR-3576 (Novuspharrna) Antitumour antibioticsDactinomycin (Actinomycin D) Amonafide Doxorubicin (Adriamycin)Azonafide Deoxyrubicin Anthrapyrazole Valrubicin OxantrazoleDaunorubicin (Daunomycin) Losoxantrone Epirubicin Bleomycin sulfate(Blenoxan) Therarubicin Bleomycinic acid Idarubicin Bleomycin ARubidazon Bleomycin B Plicamycinp Mitomycin C Porfiromycin MEN-10755(Menarini) Cyanomorpholinodoxorubicin GPX-100 (Gem Mitoxantron(Novantron) Pharmaceuticals) Antimitotic agents Paclitaxel SB 408075(GlaxoSmithKline) Docetaxel E7010 (Abbott) Colchicine PG-TXL (CellTherapeutics) Vinblastine IDN 5109 (Bayer) Vincristine A 105972 (Abbott)Vinorelbine A 204197 (Abbott) Vindesine LU 223651 (BASF) Dolastatin 10(NCI) D 24851 (ASTA Medica) Rhizoxin (Fujisawa) ER-86526 (Eisai)Mivobulin (Warner-Lambert) Combretastatin A4 (BMS) Cemadotin (BASF)Isohomohalichondrin-B RPR 109881A (Aventis) (PharmaMar) TXD 258(Aventis) ZD 6126 (AstraZeneca) Epothilone B (Novartis) PEG-Paclitaxel(Enzon) T 900607 (Tularik) AZ10992 (Asahi) T 138067 (Tularik) !DN-5109(Indena) Cryptophycin 52 (Eli Lilly) AVLB (Prescient Vinflunine (Fabre)NeuroPharma) Auristatin PE (Teikoku Azaepothilon B (BMS) Hormone) BNP-7787 (BioNumerik) BMS 247550 (BMS) CA-4-prodrug (OXiGENE) BMS 184476(BMS) Dolastatin-10 (NrH) BMS 188797 (BMS) CA-4 (OXiGENE) Taxoprexin(Protarga) Aromatase inhibitors Aminoglutethimide Exemestan LetrozoleAtamestan (BioMedicines) Anastrazole YM-511 (Yamanouchi) FormestanThymidylate Pemetrexed (Eli Lilly) Nolatrexed (Eximias) synthaseinhibitors ZD-9331 (BTG) CoFactor ™ (BioKeys) DNA antagonistsTrabectedin (PharmaMar) Mafosfamide (Baxter Glufosfamide (BaxterInternational) International) Apaziquone (Spectrum Albumin + 32P(Isotope Pharmaceuticals) Solutions) O6-benzylguanine (Paligent)Thymectacin (NewBiotics) Edotreotid (Novartis) Farnesyl transferaseArglabin (NuOncology Labs) Tipifarnib (Johnson & inhibitors lonafarnib(Schering-Ploug) Johnson) BAY-43-9006 (Bayer) Perillyl alcohol (DORBioPharma) Pump inhibitors CBT-1 (CBA Pharma) Zosuquidartrihydrochloride Tariquidar (Xenova) (Eli Lilly) MS-209 (Schering AG)Biricodar dicitrate (Vertex) Histone acetyl- Tacedinaline (Pfizer)Pivaloyloxymethyl butyrate transferase inhibitors SAHA (Aton Pharma)(Titan) MS-275 (Schering AG) Depsipeptide (Fujisawa) MetalloproteinaseNeovastat (Aeterna CMT -3 (CollaGenex) inhibitors Laboratories)BMS-275291 (Celltech) Ribonucleoside Marimastat (British Biotech)Tezacitabine (Aventis) reductase Gallium maltolate (Titan) Didox(Molecules for Health) inhibitors Triapin (Vion) TNF-alpha Virulizin(Lorus Therapeutics) Revimid (Celgene) agonists/antagonists CDC-394(Celgene) Endothelin-A Atrasentan (Abbot) YM-598 (Yamanouchi) receptorantagonists ZD-4054 (AstraZeneca) Retinoic acid receptor Fenretinide(Johnson & Alitretinoin (Ligand) agonists Johnson) LGD-1550 (Ligand)Immunomodulators Interferon Dexosome therapy (Anosys) Oncophage(Antigenics) Pentrix (Australian Cancer GMK (Progenics) Technology)Adenocarcinoma vaccine JSF-154 (Tragen) (Biomira) Cancer vaccine(Intercell) CTP-37 (AVI BioPharma) Norelin (Biostar) JRX-2 (Immuno-Rx)BLP-25 (Biomira) PEP-005 (Peplin Biotech) MGV (Progenics) Synchrovaxvaccines !3-Alethin (Dovetail) (CTL Immuno) CLL-Thera (Vasogen) Melanomavaccine (CTL Immuno) p21-RAS vaccine (GemVa Hormonal and OestrogensPrednisone antihormonal agents Conjugated oestrogens MethylprednisoloneEthynyloestradiol Prednisolone chlorotrianisene AminoglutethimideIdenestrol Leuprolide Hydroxyprogesterone caproate GoserelinMedroxyprogesterone Leuporelin Testosterone Bicalutamide Testosteronepropionate Flutamide Fluoxymesterone Octreotide MethyltestosteroneNilutamide Diethylstilbestrol Mitotan Megestrol P-04 (Novogen) Tamoxifen2-Methoxyoestradiol Toremofin (EntreMed) Dexamethasone Arzoxifen (EliLilly) Photodynamic Talaporfin (Light Sciences) Pd-Bacteriopheophorbidagents Theralux (Theratechnologies) (Yeda) Motexafin-GadoliniumLutetium-Texaphyrin (Pharmacyclics) (Pharmacyclics) Hypericin Tyrosinekinase Imatinib (Novartis) Kahalide F (PharmaMar) inhibitorsLeflunomide(Sugen/ CEP- 701 (Cephalon) Pharmacia) CEP-751 (Cephalon)ZDI839 (AstraZeneca) MLN518 (Millenium) Erlotinib (Oncogene Science)PKC412 (Novartis) Canertjnib (Pfizer) Phenoxodiol O Squalamine (Genaera)Trastuzumab (Genentech) SU5416 (Pharmacia) C225 (ImClone) SU6668(Pharmacia) rhu-Mab (Genentech) ZD4190 (AstraZeneca) MDX-H210 (Medarex)ZD6474 (AstraZeneca) 2C4 (Genentech) Vatalanib (Novartis) MDX-447(Medarex) PKI166 (Novartis) ABX-EGF (Abgenix) GW2016 (GlaxoSmithKline)IMC-1C11 (ImClone) EKB-509 (Wyeth) EKB-569 (Wyeth) Various agentsSR-27897 (CCK-A inhibitor, BCX-1777 (PNP inhibitor, Sanofi-Synthelabo)BioCryst) Tocladesine (cyclic AMP Ranpirnase (ribonuclease agonist,Ribapharm) stimulant, Alfacell) Alvocidib (CDK inhibitor, Galarubicin(RNA synthesis Aventis) inhibitor, Dong-A) CV-247 (COX-2 Inhibitor, IvyTirapazamine Medical) (reducing agent, SRI P54 (COX-2 inhibitor,International) Phytopharm) N-Acetylcysta CapCell ™ (CYP450 (reducingagent, Zambon) stimulant, Bavarian Nordic) R-Flurbiprofen (NF-kappaBGCS-IOO (gal3 antagonist, inhibitor, Encore) GlycoGenesys) 3CPA(NF-kappaB inhibitor, G17DT immunogen (gastrin Active Biotech)inhibitor, Aphton) Seocalcitol (vitamin D Efaproxiral (oxygenator, AlIOSreceptor agonist, Leo) Therapeutics) 131-I-TM-601 (DNA PI-88 (heparanaseinhibitor, antagonist, Progen) TransMolecular) Tesmilifen (histamineEflornithin (ODC inhibitor, antagonist, YM BioSciences ILEX Oncology)Histamine (histamine H2 Minodronic acid (osteoclast receptor agonist,Maxim) inhibitor, Yamanouchi) Tiazofurin (IMPDH inhibitor, Indisulam(p53 stimulant, Ribapharm) Eisai) Cilengitide (integrin antagonist,Aplidin (PPT inhibitor, Merck KGaA) PharmaMar) SR-31747 (IL-1antagonist, Rituximab (CD20 antibody, Sanofi-Synthelabo) Genentech)CCI-779 (mTOR kinase Gemtuzumab (CD33 inhibitor, Wyeth) antibody, WyethAyerst) Exisulind (PDE-V inhibitor, PG2 (haematopoiesis Cell Pathways)promoter, Pharmagenesis) CP-461 (PDE-V inhibitor, Cell Immunol ™(triclosan Pathways) mouthwash, Endo) AG-2037 (GART inhibitor,Triacetyluridine (uridine prodrug Pfizer) Wellstat) WX-UK1 SN-4071(sarcoma agent, (plasminogen activator Signature BioScience) inhibitor,Wilex) TransMID-107 ™ PBI-1402 (PMN stimulant, (immunotoxin, KSBiomedix) ProMetic LifeSciences) PCK-3145 (apoptosis Bortezomib(proteasome promoter, Procyon) inhibitor, Millennium) Doranidazole(apoptosis SRL-172 (T-cell stimulant, promoter, Pola) SR Pharma) CHS-828(cytotoxic TLK-286 (glutathione-S agent, Leo) transferase inhibitor,Telik) trans-Retinic acid PT-100 (growth factor (differentiator, NIH)agonist, Point Therapeutics) MX6 (apoptosis promoter, Midostaurin (PKCinhibitor, MAXIA) Novartis) Apomine (apoptosis promoter, Bryostatin-1(PKC stimulant, ILEX Oncology) GPC Biotech) Urocidin (apoptosispromoter, CDA-II (apoptosis promoter, Bioniche) Everlife) Ro-31-7453(apoptosis SDX-101 (apoptosis promoter, promoter, La Roche) Salmedix)Brostallicin (apoptosis Ceflatonin (apoptosis promoter, Pharmacia)promoter, ChemGenex)

A combined treatment of this type can be achieved with the aid ofsimultaneous, consecutive or separate dispensing of the individualcomponents of the treatment. Combination products of this type employthe compounds according to the invention.

Assays

The compounds of the formula I described in the examples were tested inthe assays described below, and it was found that they have akinase-inhibiting activity. Other assays are known from the literatureand could readily be performed by the person skilled in the art (see,for example, Dhanabal et al., Cancer Res. 59:189-197; Xin et al., J.Biol. Chem. 274:9116-9121; Sheu et al., Anticancer Res. 18:4435-4441;Ausprunk et al., Dev. Biol. 38:237-248; Gimbrone et al., J. Natl. CancerInst. 52:413-427; Nicosia et al., In Vitro 18:538-549).

Description of the Method for the Cellular Testing of PI3K Inhibitors

The measure used for the cellular PI3K activity is the PI3K-dependentphosphorylation of PKB at Serin 473. The cellular assay fordetermination of the P-S473-PKB level is carried out as a Luminex assayin 96-well format in PC3 cells. PC3 cells exhibit constitutivephosphorylation of PKB owing to a PTEN mutation.

PC3 cells are sown out with 20,000 cells per well in 100 μl medium (45%RPMI1460/45% Ham's F12/10% FCS) and incubated on the following day for30 min with a serial dilution of the test substance (7 concentrations)under serum-free conditions. The cells are subsequently lysed using 90μl of lysis buffer (20 mM Tris/HCl pH 8.0, 150 mM NaCl, 1% NP40, 10%glycerol, 1% phosphatase inhibitor I, 1% phosphatase inhibitor II, 0.1%protease inhibitor cocktail III, 0.01% benzonase) per well, and thelysates are separated off from insoluble cell constituents by means ofcentrifugation through a 96-well filter plate (0.65 μm). The lysates areincubated overnight at 4° C. with shaking with Luminex beads to which ananti-total PKB antibody is coupled. The detection is carried out on thefollowing day by addition of a P-S473-PKB antibody and aspecies-specific PE-labelled secondary antibody. The detection ofP-S473-PKB is carried out by measurement in a Luminex 100 instrument bydetermination of 100 events per cavity in a measurement time of 60 sec.As pharmacological blank, the signals obtained from cells which havebeen treated with 3 μM wortmannin are subtracted from all otherpreparations. The control value used for maximum phosphorylation of PKBat S473 are the signals from cells which have been treated only with thesolvent (0.3% DMSO). The values of the preparations treated with testsubstance are calculated from this as percent of control, and IC50values are determined by means of RS1.

Above and below, all temperatures are indicated in ° C. In the followingexamples, “conventional work-up” means: water is added if necessary, thepH is adjusted, if necessary, to values between 2 and 10, depending onthe constitution of the end product, the mixture is extracted with ethylacetate or dichloromethane, the phases are separated, the organic phaseis dried over sodium sulfate, evaporated and purified by chromatographyon silica gel and/or by crystallisation. Rf values on silica gel;eluent: ethyl acetate/methanol 9:1.

-   Mass spectrometry (MS): EI (electron impact ionisation) M⁺    -   FAB (fast atom bombardment) (M+H)⁺-   ESI (electrospray ionisation) (M+H)⁺-   APCI-MS (atmospheric pressure chemical ionisation-mass spectrometry)    (M+H)⁺.-   HPLC-MS:-   Agilent 1200 series instrument

HPLC-MS Esi1.Rod.m/Polar.m/Nonpolar.m methods Column Chromolith SpeedRod RP 18e 50-4.6 mm Flow rate 2.4 ml/min Buffer A 0.05% of formicacid/water Buffer B 0.04% of formic acid/acetonitrile Wavelength 220 nmGradient 0.0-2.8 min 4%-100% of buffer B; 2.8-3.3 min 100% of Polar.mbuffer B; 3.3-3.4 min 100%-4

-   LC-MS method: polar:-   Column: Chromolith Speed Rod RP 18e 50-4.6 mm LCMS-   Polar.m, 2.4 ml/min, 220 nm, buffer A 0.05% of HCOOH/H₂O, buffer B    0.04% of HCOOH/ACN, 0.0-3.0 min 5%-100% of buffer B; 3.0-3.5 min    100% of buffer B-   Polar 1: Agilent 1200 series instrument-   Polar 2: Agilent 1100 series instrument-   Retention time R_(f) in minutes [min].

The compounds according to the invention can be prepared by thefollowing synthesis sequences (AAV1 and AAV2):

-   AAV Method 1:

1 equivalent of the sulfonamide or of the alkali-metal salt of thesulfonamide are stirred with 0.9-1.5 equivalents of2,3-dichloroquinoxaline in a reaction flask with reflux condenser in thepresence of 0.1-3 equivalents of an alkali-metal or alkaline-earth metalcarbonate in DMA at temperatures between 30° C. and 180° C. withexclusion of water, preferably under protective gas, until thesulfonamide has reacted virtually completely (about 0.5-12 hours). Thecooled reaction mixture is added to water and filtered off with suction.The filtrate is acidified, cooled, and the newly formed precipitate isfiltered off with suction, rinsed with suitable solvents and dried. Ifnecessary, this can be followed by purification methods known to theperson skilled in the art, such as, for example, recrystallisations orchromatographies.

AAV Method 2: (General Procedure)

1 equivalent of the quinoxaline derivative, 0.9-2.5 equivalents of theamine in 30-100 equivalents of 1-propanol or a comparable alcohol(1-butanol, 2-propanol, ethanol, etc.) or another organic solvent, suchas ethyl glycol, dioxane, THF, are heated in a microwave-suitable glassvessel at 40-180° C. with high absorption in the microwave until thequinoxaline derivative has reacted virtually completely (about 1-12hours). The cooled reaction mixture is filtered off with suction, rinsedwith 1-propanol and dried. If necessary, this can be followed bypurification methods known to the person skilled in the art, such as,for example, recrystallisations or chromatographies.

This method may in addition be followed by further synthesis steps,which are explained in the examples.

The sulfonamides required for the first step are either commerciallyavailable or can be prepared by methods known to the person skilled inthe art, for example by aminolysis from the corresponding sulfonylchlorides.

EXAMPLE 1 Preparation of 1-methyl-1H-pyrazole-3-sulfonic acid(3-chloroquinoxalin-2-yl) amide (building block for the preparation ofA24)

2.0 g of 1-methyl-1H-pyrazole-3-sulfonamide and 812 mg of KOH (content84%, remainder water) are stirred in about 20 ml of water in a flaskuntil a clear solution has formed. This is lyophilised for completeremoval of the water. The solid potassium salt is heated with 2.74 g of2,3-dichloroquinoxaline and 866 mg of potassium carbonate in about 20 mlof dried DMA under nitrogen at 120° C. (bath temperature) until thesulfonamide has reacted virtually completely (HPLC check, about 3hours). The cooled reaction solution is poured into about 200 ml ofice-water, with a precipitate depositing after some time. This isfiltered off with suction and discarded. The filtrate is adjusted to pH4-5 using saturated citric acid solution. A further precipitatedeposits, which is filtered off, washed with water and dried, giving3.36 g of 1-methyl-1H-pyrazole-3-sulfonic acid (3-chloroquinoxalin-2-yl)amide as pale-beige solid (yield 86%, content 97%). MS-FAB (M+H⁺)=324.0.R_(f) (polar method): 1.85 min. This is employed without furtherpurification for the next step.

A similar procedure enables numerous other sulfonamides to be convertedinto corresponding quinoxaline derivatives: prior separate preparationof the potassium salts is not absolutely necessary, but in some casesresults in better yields. If the preparation of the potassium salt isomitted, the corresponding amount of potassium carbonate must beincreased to 0.9-2.5 equivalents. Instead of potassium carbonate, it isalso possible to employ other alkali-metal or alkaline-earth metalcarbonates taking into account the base equivalents).

EXAMPLE 2 Preparation of2-[3-(3-chloroquinoxalin-2-ylsulfamoyl)pyrazol-1-yl]-2,2-difluoro-N,N-dimethylacetamide(building block for the preparation of A 119)

1.30 g of2,2-difluoro-N,N-dimethyl-2-(3-sulfamoylpyrazol-1-yl)acetamide, 1.16 gof 2,3-dichloroquinoxaline and 670 mg of potassium carbonate in about 16ml of dried DMA are heated at 100° C. (bath temperature) under nitrogenin a flask until the sulfonamide has reacted virtually completely (HPLCcheck, about 3 hours). The cooled reaction solution is poured into about200 ml of ice-water, with a precipitate depositing after some time. Thisis filtered off with suction and discarded. The filtrate is adjusted topH 4-5 using saturated citric acid solution. A further precipitatedeposits, which is filtered off, washed with water and dried, giving1.44 g of2-[3-(3-chloroquinoxalin-2-ylsulfamoyl)pyrazol-1-yl]-2,2-difluoro-N,N-dimethylacetamideas pale-beige solid (yield 69%, content 99.8%). MS-FAB (M+H⁺)=431.0.R_(f) (polar method): 1.98 min. This is employed without furtherpurification for the next step.

The following can be employed, for example (without restricting theprocess thereto)

EXAMPLE 3 Preparation of2,2-difluoro-2-(3-{3-[2-(3-hydroxybutoxy)-3,5-dimethoxy-phenylamino]-quinoxalin-2-ylsulfamoyl}pyrazol-1-yl)-N,N-dimethylacetamide(“A118”)

300 mg of2-[3-(3-chloroquinoxalin-2-ylsulfamoyl)pyrazol-1-yl]-2,2-difluoro-N,N-dimethylacetamideand 258 mg of 4-(2-amino-4,6-dimethoxyphenoxy)butan-2-ol in 4 ml of1-propanol are heated at 140° C. in a microwave-suitable glass vesselwith high absorption in the microwave until starting material 1 hasreacted virtually completely (about 45 minutes). The cooled reactionmixture is filtered off with suction, rinsed with 1-propanol and dried,giving 320 mg of2,2-difluoro-2-(3-{3-[2-(3-hydroxybutoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-ylsulfamoyl}pyrazol-1-yl)-N,N-dimethylacetamideas slightly yellowish solid (yield 74%). MS-FAB (M+H⁺)=636.2. R_(f)(polar method): 2.41 min.

Compounds A1-A22, A24-A37, A39-A56, A58-A92, A93-A105, A107, A107,A112-A115, A117-A128 and A131 are obtained by this method from thecorresponding quinoxaline derivatives and amines:

HPLC Compound R_(f) [min]/ MS-FAB No. Name and/or structure method [M +H]⁺ “A1”

2.24/ polar 1 455.46 “A2”

1.83/ polar 1 547.64 “A3”

2.15/ polar 1 637.75 “A4”

1.86/ polar 1 616.73 “A5”

2.07/ polar 1 483.51 ¹H NMR (500 MHz, DMSO-d₆ + TFA-d₁): δ [ppm] 8.58(s, 1H), 8.23 (d, J = 1.3 Hz, 1H), 8.08 (d, J = 2.2 Hz, 1H), 7.90 (dd, J= 1.8, 7.6 Hz, 1H), 7.70 (dd, J = 2.2, 7.1 Hz, 1H), 7.48-7.41 (m, 2H),6.66 (d, J = 2.5 Hz, 1H), 4.98-4.91 (m, 1H), 3.84 (s, 3H), 3.79 (s, 3H),3.70 (dd, J = 3.8, 12.0 Hz, 1H), 3.62 (dd, J = 5.4, 12.1 Hz, 1H), 3.28(dd, J = 9.5, 15.5 Hz, 1H), 3.11 (dd, J = 7.4, 16.0 Hz, 1H) “A6”

2.44/ polar 1 534.60 “A7”

2.18/ polar 1 513.58 “A8”

2.47/ polar 1 535.6  “A9”

2.21/ polar 1 522.55 “A10”

2.37/ polar 1 469.49 “A11”

2.47/ polar 1 455.50 “A12”

2.57/ polar 1 522.6  “A13”

2.57 536.6  “A14”

2.46 469.5  “A15”

2.35 518.6  “A16” 1-Methyl-1H-imidazole-4-sulfonic acid[3-(5-methoxybenzofuran-7-ylamino) 2.25/ 451.6 quinoxalin-2-yl]amidepolar 2 “A17”

1.76/ polar 1 469.5  “A1 “A18”

2.53/ polar 2 536.6  “A19”

2.37/ polar 1 520.4  “A20”

2.35/ polar 1 475.9  “A21”

2.19/ polar 1 512.6  “A22”

2.28/ polar 1 518.58 “A24”

2.27/ polar 515.1  “A25”

2.21/ polar 1 449.49 “A26”

2.48/ polar 1 541.59 “A27”

2.14/ polar 1 586.63 “A28”

1.72/ polar 1 586.68 “A29”

2.37/ polar 1 551.54 “A30”

2.50/ polar 1 511.56 “A31”

1.77/ polar 1 528.60 “A32”

2.27/ polar 1 529.58 “A33”

1.70/ polar 1 572.65 “A34”

2.43/ polar 1 598.64 “A35”

2.19/ polar 1 553.62 “A36”

2.10/ polar 555.64 “A39”

2.43/ polar 1 503.46 “A40”

2.65/ polar 1 459.41 “A41”

2.61/ polar 1 590.67 “A42”

2.22/ polar 1 529.58 “A43”

2.26/ polar 1 529.58 ¹H NMR (500 MHz, DMSO-d₆ +TFA-d₁): δ [ppm] 8.47 (s,1H), 8.26 (d, J = 2.8, 1H), 8.04-7.95 (m, 2H), 7.65 (dd, J = 7.7, 1.6,1H), 7.40 (pd, J = 7.2, 1.6, 2H), 6.41 (d, J = 2.8, 1H), 4.00 (t, J =7.1, 2.H), 3.90 (s, 3H), 3.86-3.77 (m, 7H), 1.76 (q, J = 6.9, 2H), 1.10(d, J = 6.2, 3H) “A44”

2.19/ polar 1 515.56 “A45”

2.47/ polar 1 550.60 “A46”

2.56/ polar 1 536.57 “A47”

2.26/ polar 1 559.61 “A48”

2.56/ polar 1 580.63 “A49”

2.40/ polar 1 533.49 “A50”

2.23/ polar 1 568.62 “A51”

2.44/ polar 1 542.60 “A52”

2.06/ polar 1 547.62 “A53”

2.41/ polar 1 559.58 “A54”

 1.7/ polar 1 570.63 “A55”

2.21/ polar 1 563.62 “A56”

2.30/ polar 1 507.57 “A58”

2.38/ polar 1 541.59 “A59”

2.38/ polar 1 572.63 “A60”

1.80/ polar 1 560.66 “A61”

2.41/ polar 1 571.62 ¹H NMR (500 MHz, DMSO-d₆ + TFA-d₁): δ [ppm] 8.23(d, J = 2.8 Hz, 1H), 8.06-8.01 (m, 2H), 8.00-7.96 (m, 1H), 7.63 (dd, J =1.8, 7.6 Hz, 1H), 7.43-7.35 (m, 2H), 7.14 (d, J = 8.9 Hz, 2H), 6.39 (d,J = 2.7 Hz, 1H), 4.02 (t, J = 5.0 Hz, 2H), 3.86 (s, 3H), 3.83 (s, 3H),3.82 (s, 3H), 3.53 (t, J = 5.0 Hz, 2H), 3.43 (t, J = 5.1 Hz, 2H), 3.37(t, J = 5.1 Hz, 2H) “A62”

2.18/ polar 1 598.64 ¹H NMR (500 MHz, DMSO-d₆ + TFA-d₁): δ [ppm] 8.24(d, J = 2.8, 1H), 8.05-8.00 (m, 2H), 7.98 (dd, J = 1.7, 7.7, 1H), 7.83(d, J = 8.8, 2H), 7.64 (dd, J = 1.7, 7.7, 1H), 7.43-7.35 (m, 2H), 6.40(d, J = 2.8, 1.H), 4.02 (t, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 3.51 (t, J= 5.0, 2H), 3.44 (t, J = 5.2, 2H), 3.36 (t, J = 5.2, 2H), 3.37 (s, 3H)“A63”

2.36/ polar 1 566.60 ¹H NMR (500 MHz, DMSO-d₆ + TFA-d₁): δ [ppm] 8.59(t, J = 1.5, 1H), 8.44-8.39 (m, 1H), 8.27 (d, J = 2.8, 1H), 8.13-8.08(m, 1H), 7.99 (dd, J = 1.5, 7.9, 1H), 7.84 (t, J = 7.9, 1H), 7.68 (dd, J= 1.5, 7.8, 1H), 7.47-7.37 (m, 2H), 6.41 (d, J = 2.7, 1H), 4.07 (t, J =4.8, 2H), 3.84 (s, 6H), 3.52 (t, J = 4.8, 2H), 3.45 (t, J = 5.2, 2H),3.38 (t, J = 5.2 2H) “A64”

2.35/ polar 1 547.62 ¹H NMR (500 MHz, DMSO-d₆ + TFA-d₁): δ [ppm] 8.25(d, J = 2.8 Hz, 1H), 8.04 (dd, J = 1.4, 7.9 Hz, 1H), 7.97- 7.92 (m, 2H),7.66 (dd, J = 1.4, 7.9 Hz, 1H), 7.46-7.37 (m, 2H), 7.19 (dd, J = 3.9,4.8 Hz, 1H), 6.41 (d, J = 2.7 Hz, 1H), 4.08 (t, J = 5.0 Hz, 2H), 3.85(s, 3H), 3.84 (s, 3H), 3.64 (t, J = 5.0 Hz, 2H), 3.48-3.41 (m, 4H) “A65”

2.17/ polar 1 542.58 ¹H NMR (500 MHz, DMSO-d₆ + TFA-d₁): δ [ppm] 9.41(d, J = 1.7 Hz, 1H), 8.97 (dd, J = 1.4, 5.2 Hz, 1H), 8.79- 8.73 (m, 1H),8.22 (d, J = 2.8 Hz, 1H), 7.99 (dd, J = 1.4, 7.9 Hz, 1H), 7.92 (dd, J =5.3, 8.1 Hz, 1H), 7.67 (dd, J = 1.4, 7.9 Hz, 1H), 7.43 (dtd, J = 1.5,7.3, 16.8 Hz, 2H), 6.41 (d, J = 2.8 Hz, 1H), 4.04 (t, J = 4.8 Hz, 2H),3.83 (s, 3H), 3.82 (s, 3H), 3.52 (t, J = 4.8 Hz, 2H), 3.43 (t, J = 5.3Hz, 2H), 3.37 (t, J = 5.0 Hz, 2H) “A66”

2.39/ polar 1 503.56 ¹H NMR (500 MHz, DMSO-d₆ + TFA-d₁): δ [ppm] 8.24(d, J = 2.8 Hz, 1H), 8.03 (dd, J = 1.6, 7.8 Hz, 1H), 7.96 (dd, J = 1.3,3.7 Hz, 1H), 7.92 (d, J = 4.9 Hz, 1H), 7.66 (dd, J = 1.5, 7.8 Hz, 1H),7.45-7.36 (m, 2H), 7.19 (dd, J = 3.8, 4.9 Hz, 1H), 6.42 (d, J = 2.7 Hz,1H), 3.98 (t, J = 5.6 Hz, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 3.66(t, J =5.6 Hz, 2H) “A67”

2.12/ polar 1 590.64 ¹H NMR (500 MHz, DMSO-d₆ + TFA-d₁): δ [ppm] 9.47(d, J = 2.0 Hz, 1H), 9.00 (dd, J = 1.3, 5.2 Hz, 1H), 8.89- 8.81 (m, 1H),8.12 (d, J = 2.7 Hz, 1H), 8.02 (dd, J = 1.4, 7.9 Hz, 1H), 7.97 (dd, J =5.3, 8.1 Hz, 1H), 7.69 (dd, J = 1.4, 7.8 Hz, 1H), 7.51-7.38 (m, 2H),6.46 (d, J = 2.7 Hz, 1H), 4.29 (t, J = 6.4 Hz, 2H), 3.87 (s, 3H), 3.87-3.81 (m, 5H), 3.50 (t, J = 6.4 Hz, 2H), 3.33 (t, J = 5.9 Hz, 2H) “A68”

1.69/ polar 1 555.62 “A69”

2.18/ polar 1 612.67 ¹H NMR (500 MHz, DMSO-d₆ + TFA-d₁): δ [ppm] 8.26(d, J = 2.8 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 8.00 (dd, J = 1.5, 7.9Hz, 1H), 7.71-7.61 (m, 3H), 7.47-7.37 (m, 2H), 6.41 (d, J = 2.8 Hz, 1H),4.05 (t, J = 4.9 Hz, 2H), 3.84 (s, 6H), 3.53 (t, J = 4.9 Hz, 2H), 3.43(t, J = 5.1 Hz, 2H), 3.37 (t, J = 5.1 Hz, 2H), 3.04 (s, 3H), 2.93 (s,3H) “A70”

1.88/ polar 1 591.65 ¹H NMR (500 MHz, DMSO-d₆ + TFA-d₁): δ [ppm]8.33-8.27 (m, 2H), 8.14 (d, J = 2.8 Hz, 1H), 8.13-8.07 (m, 2H), 8.04(dd, J = 1.5, 8.0 Hz, 1H), 7.68 (dd, J = 1.4, 7.9 Hz, 1H), 7.44 (dtd, J= 1.5, 7.3, 15.1 Hz, 2H), 6.47 (d, J = 2.8 Hz, 1H), 4.19 (t, J = 4.94Hz, 2H), 4.06 (d, J = 11.8 Hz, 2H), 3.87 (s, 3H), 3.84 (s, 3H), 3.80 (t,J = 11.8 Hz, 2H), 3.56 (d, J = 12.3 Hz, 2H), 3.44 (t, J = 5.0 Hz, 2H),3.25 (td, J = 3.5, 12.5 Hz, 2H) “A71”

2.55/ polar 1 547.54 “A72”

2.19/ polar 1 598.67 ¹H NMR (500 MHz, DMSO-d₆ + TFA-d₁): δ [ppm] 8.27(d, J = 8.5 Hz, 2H), 8.18 (d, J = 2.8 Hz, 1H), 8.08 (dd, J = 1.3, 8.4Hz, 2H), 8.00 (dd, J = 1.2, 7.9 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H),7.48-7.37 (m, 2H), 6.42 (d, J = 2.5 Hz, 1H), 4.28 (ddd, J = 5.5, 8.0,10.7 Hz, 1H), 4.18 (dt, J = 5.6, 11.0 Hz, 1H), 3.84 (s, 3H), 3.83 (s,3H), 3.79 (dt, J = 5.9, 12.3 Hz, 2H), 3.12-3.02 (m, 1H), 2.95 (ddd, J =4.3, 7.8, 14.1Hz, 2H), 2.83 (dt, J = 4.5, 13.2 Hz, 1H) “A73”

2.49 polar 1 577.57 “A74”

2.26/ polar 1 552.57 ¹H NMR (500 MHz, DMSO-d₆ + TFA-d₁): δ [ppm] 8.31(d, J = 8.5 Hz, 2H), 8.21 (d, J = 2.8 Hz, 1H), 8.07 (d, J = 8.6 Hz, 2H),7.99 (dd, J = 1.4, 7.9 Hz, 1H), 7.65 (dd, J = 1.4, 7.8 Hz, 1H),7.46-7.37 (m, 2H), 6.41 (d, J = 2.8 Hz, 1H), 3.96 (dd, J = 4.5, 10.3 Hz,1H), 3.85-381 (m, 7H), 3.66-3.60 (m, 1H), 3.41-3.33 (m, 2H) “A75”

2.00/ polar 1 531.55 ¹H NMR (500 MHz, DMSO-d₆ + TFA-d₁): δ [ppm] 8.62(s, 1H), 8.22 (d, J = 1.7Hz, 2H), 7.92 (dd, J = 1.5, 7.9 Hz, 1H), 7.69(dd, J = 1.5, 7.9 Hz, 1H), 7.49-7.39 (m, 2H), 6.44 (d, J = 2.9 Hz, 1H),4.03 (dd, J = 4.4, 10.3 Hz, 1H), 3.89-3.85 (m, 4H), 3.85 (s, 3H), 3.84(s, 3H), 3.75 (td, J = 5.3, 10.0 Hz, 1H), 3.47 (qd, J = 5.3, 11.2 Hz,2H) “A76”

2.33/ polar 1 614.66 ¹H NMR (500 MHz, DMSO-d₆ + TFA-d₁): δ [ppm]8.34-8.27 (m, 2H), 8.17 (d, J = 2.8 Hz, 1H), 8.11-8.05 (m, 2H), 8.03(dd, J = 1.6, 7.9 Hz, 1H), 7.68 (dd, J = 1.5, 7.8 Hz, 1H), 7.48-7.38 (m,2H), 6.44 (d, J = 2.8 Hz, 1H), 4.27 (t, J = 6.5 Hz, 2H), 3.87 (s, 3H),3.86-3.82 (m, 5H), 3.44 (t, J = 6.5 Hz, 2H), 3.32 (t, J = 5.9 Hz, 2H)“A77”

2.09/ polar 1 593.65 ¹H NMR (500 MHz, DMSO-d₆ + TFA-d₁): δ [ppm] 8.54(d, J = 0.7 Hz, 1H), 8.21 (d, J = 1.3 Hz, 1H), 8.18 (d, J = 2.8 Hz, 1H),7.93 (dd, J = 1.6, 7.8 Hz, 1H), 7.71 (dd, J = 1.6, 7.8 Hz, 1H), 7.45(pd, J = 1.6, 7.3 Hz, 2H), 6.45 (d, J = 2.8 Hz, 1H), 4.31 (t, J = 6.5Hz, 2H), 3.89-3.86 (m, 5H), 3.85 (s, 3H), 3.84 (s, 3H), 3.57 (t, J = 6.6Hz, 2H), 3.37 (t, J = 6.0 Hz, 2H) “A78”

1.84/ polar 1 579.64 “A79”

2.22/ polar 1 512.55 “A80”

2.37/ polar 1 566.60 ¹H NMR (500 MHz, DMSO-d₆ + TFA-d₁): δ [ppm]8.33-8.26 (m, 2H), 8.25 (d, J = 2.8 Hz, 1H), 8.16-8.07 (m, 2H), 8.01(dd, J = 1.6, 7.9 Hz, 1H), 7.67 (dd, J = 1.6, 7.8 Hz, 1H), 7.43 (pd, J =1.6, 7.3 Hz, 2H), 6.41 (d, J = 2.8 Hz, 1H), 4.07-3.97 (t, J = 4.8 Hz,2H), 3.83 (s, 6H), 3.52-3.45 (m, 2H), 3.43 (t, J = 5.1 Hz, 2H), 3.35 (t,J = 5.3 Hz, 2H “A81”

2.09/ polar 1 545.58 ¹H NMR (500 MHz, DMSO-d₆ + TFA-d₁): δ [ppm] 8.52(s, 1H), 8.22 (d, J = 2.8 Hz, 1H), 8.20 (d, J = 1.3 Hz, 1H), 7.91-7.87(m, 1H), 7.71-7.68 (m, 1H), 7.48-7.40 (m, 2H), 6.42 (d, J = 2.9 Hz, 1H),4.08 (t, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 3.83 (s, 3H), 3.66 (t, J = 4.9Hz, 2H), 3.49-3.39 (m, 4H) “A82”

2.42/ polar 1 536.57 ¹H NMR (500 MHz, DMSO-d₆ + TFA-d₁): δ [ppm] 8.25(m, 3H), 8.09 (d, J = 8.6 Hz, 2H), 8.01 (dd, J = 1.5, 7.9 Hz, 1H), 7.67(dd, J = 1.4, 7.9 Hz, 1H), 7.50-7.36 (m, 2H), 6.40 (d, J = 2.8 Hz, 1H),3.90 (t, J = 7.0 Hz, 2H), 3.82 (d, J = 3.1 Hz, 6H), 3.40 (t, J = 6.2 Hz,2H), 1.59 (p, J = 6.6, 2H) “A83”

2.39/ polar 1 507.5  “A84”

2.76/ polar 1 528.5  “A85”

2.54/ polar 1 574.6  “A86”

2.23/ polar 1 515.56 “A87”

2.31/ polar 1 582.6  “A88”

2.29/ polar 1 501.53 “A89”

2.18/ polar 1 501.53 “A90”

2.33/ polar 2 538.6  “A91”

2.62/ polar 1 492.52 “A92”

2.26/ polar 1 471.50 “A93”

2.37/ polar 618.6  “A94”

1.71/ polar 570.7  “A95”

2.46/ polar 636.6  “A96”

2.21/ polar 488.5  “A97”

2.26/ polar 582.6  “A98”

2.41/ polar 630.6  “A99”

2.27/ polar 463.5  “A100”

2.33/ polar 529.6  “A101”

2.25 polar 532.6  “A102”

2.27/ polar 594.7  “A103”

2.45/ polar 565.6  “A104”

2.35/ polar 478.5  “A105”

2.46/ polar 636.6  “A107”

2.10/ polar 630.6  “A108”

2.27/ polar 594.7  “A112”

2.18/ polar 545.6  “A113”

1.73/ polar 586.7  “A114”

2.35/ polar 485.5  “A115”

2.43/ polar 499.5  “A117”

2.28/ polar 513.6  “A119”

2.35/ polar 622.6  “A120”

2.21/ polar 600.7  “A121”

2.41/ polar 471.5  “A122”

2.14/ polar 586.6  “A123”

1.76/ polar 614.7  “A124”

2.06/ polar 499.5  “A125”

2.37/ polar 543.6  “A126”

1.78/ polar 600.7  “A127”

2.14/ polar 499.5  “A128”

1.76/ polar 600.7  “A131”

2.29/ polar 542.6 Examples of the Preparation of Amine Building Blocks:

Preparation of the aniline building block for “A6”, “A7”:

Preparation of the aniline building block for “A5”:

Preparation of the aniline building block for “A15” and “A16”:

Preparation of the aniline building block for “A124” and “A127”:

EXAMPLE 4 Preparation of4-dimethylaminomethyl-N-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}benzenesulfonamide(“A38”)

A total of 4 equivalents of LiAlH₄, dissolved in THF, are added to 200mg of4-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-ylsulfamoyl}-N,N-dimethylbenzamide,dissolved in about 10 ml of THF, at 0° C. (ice bath) in a multineckedflask which has been dried by heating, and the mixture is stirred at RTuntil the starting material has reacted virtually completely (severalhours, HPLC check). The reaction mixture is quenched by addition of 5 mlof methanol. The solution is acidified until everything dissolves,evaporated somewhat and purified by preparative HPLC on silica gel RP18(acetonitrile, water), giving 75 mg of4-dimethylaminomethyl-N-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}benzenesulfonamideas yellow solid (yield 36%); MS-FAB (M+H⁺)=568.2; R_(f) (polar method):1.85 min.

The following compounds are obtained analogously:

HPLC Compound R_(f) [min]/ MS-FAB No. Name and/or structure method [M +H]⁺ “A23”  1-(2-Dimethylamino-ethyl)-1H-pyrazole-4- 1.76/  572.65sulfonic acid {3-[2-(3-hydroxypropoxy)-3,5- polar 1dimethoxy-phenylamino]quinoxalin-2-yl} amide

“A57”  4-Dimethylaminomethyl-N-(3-{2-[2-(2-hydroxy- 1.76/  598.68ethoxy)ethoxy]-3,5-dimethoxyphenylamino}- polar 1quinoxalin-2-yl)benzenesulfonamide

¹H NMR (500 MHz, DMSO-d₆ + TFA-d₁) δ 8 ppm] 8.25 (d, J = 2.8, 1H), 8.20(d, J = 8.3, 2H), 8.02-7.97 (m, 1H), 7.77 (d, J = 8.3, 2H), 7.69-7.64(m, 1H), 7.47-7.36 (m, 2H), 6.40 (d, J = 2.8, 1H), 4.42 (s, 2H),4.07-3.98 (m, 2H), 3.83 (s, 6H), 3.54-3.47 (m, 2H), 3.43 (t, J = 5.2,2H), 3.37 (t, J = 5.2, 2H), 2.79 (s, 6H) “A109”3-Dimethylaminomethyl-N-{3-[2-(3-hydroxy- 1.79/ 568.7propoxy)-3,5-dimethoxyphenylamino]quinoxalin- polar2-yl}benzenesulfonamide

“A110” 4-(3,3-Difluoroazetidin-1-ylmethyl)-N-{3-[2-(3- 2.30/ 616.7hydroxypropoxy)-3,5-dimethoxyphenylamino]- polarquinoxalin-2-yl}benzenesulfonamide

“A111” 4-Azetidin-1-ylmethyl-N-{3-[2-(3- 1.78/ 580.7hydroxypropoxy)-3,5-dimethoxyphenylamino]- polarquinoxalin-2-yl}-benzenesulfonamide

“A116” 3-Azetidin-1-ylmethyl-N-{3-[2-(3- 1.80/ 580.7hydroxypropoxy)-3,5-dimethoxyphenylamino]- polarquinoxalin-2-yl}-benzenesulfonamide

“A129” 1-(2-Dimethylaminoethyl)-1H-pyrazole-3-sulfonic 1.77/ 586.7 acid{3-[2-(3-hydroxybutoxy)-3,5-dimethoxy- polarphenylamino]quinoxalin-2-yl} amide

“A130” 1-(2-Dimethylaminoethyl)-1H-pyrazole-3-sulfonic 1.74/ 572.7 acid{3-[2-(3-hydroxypropoxy)-3,5-dimethoxy- polarphenylamino]quinoxalin-2-yl} amide

EXAMPLE 5 Preparation of4-aminomethyl-N-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxy-phenylamino]-quinoxalin-2-yl}benzenesulfonamide(“A 106”)

1.15 g of4-cyano-N-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}-benzenesulfonamidein 5 ml of THF and 12 ml of methanolic ammonia solution (10%) arehydrogenated in a suitable pressure apparatus in the presence of 1.00 gof sponge nickel catalyst (Johnson-Matthey) at 50° C. and 5 bar for 17hours. The catalyst is filtered off, rinsed with copious MeOH and THF,and the entire filtrate is evaporated, giving 819 mg of4-aminomethyl-N-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}-benzenesulfonamidehaving a content of 82.4% (yield 59.4%); MS-FAB (M+H⁺)=540.2; R_(f)(polar method): 1.75 min.

EXAMPLE 6 Preparation ofN-(4-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-ylsulfamoyl}benzyl)acetamide(“A132”)

100 mg of4-aminomethyl-N-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]-quinoxalin-2-yl}benzenesulfonamide(content 82%), 37 mg of DAPECI and 8.7 l of acetic acid in 1 ml of DMFare stirred at RT overnight in a screw-cap vial. The reaction solutionis poured into water, and the deposited precipitate is filtered off withsuction. Purification by preparative HPLC on silica gel RP18(acetonitrile, water) gives a total of 39 mg ofN-(4-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-ylsulfamoyl}benzyl)acetamide(yield 41%); MS-FAB (M+H⁺)=582.2; R_(f) (polar method): 2.19 min.

-   Pharmacological Data-   PI3 Kinase Inhibition

Compared with other quinoxaline derivatives disclosed in WO 2008/101979,the compounds according to the invention have improved inhibitingproperties on PI3 kinase.

TABLE 1 IC₅₀ IC₅₀ Compound No. (cell) Compounds from WO 2008/101979(cell)

 96 nM

 370 nM

4.6 nM

1100 nM

 38 nM

4900 nM

 53 nM

 970 nM

1.4 nM

 290 nM

 86 nM

2600 nM

 96 nM

 985 nMPI3 Kinase Inhibition

TABLE 2 Compound IC₅₀ IC₅₀ Compound IC₅₀ IC₅₀ No. (enzyme) (cell) No.(enzyme) (cell) “A1” B “A46” “A2” B “A47” A “A3” A “A48” A “A4” B “A49”A “A5” B “A50” A “A6” A “A51” A “A7” B “A52” B “A8” “A53” A “A9” B “A54”B “A10” B “A55” A “A11” B “A56” B “A12” B “A57” B “A13” B “A58” A “A14”B “A59” A “A15” C “A60” A “A16” C “A61” B “A17” C “A62” B “A18” C “A63”B “A19” “A64” A “A20” “A65” B “A21” C “A66” A “A22” A “A67” B “A23” B“A68” B “A69” B “A25” B “A70” A “A26” B “A71” A “A27” B “A72” A “A28” A“A73” B “A29” A “A74” A “A30” A “A75” B “A31” B “A76” A “A32” B “A77” B“A33” B “A78” A “A34” B “A79” B “A35” A “A80” A “A36” A “A81” B “A82” A“A38” A “A86” A “A39” A “A88” B “A40” A “A89” A “A41” A “A90” B “A42” A“A91” A “A43” B “A92” B “A44” A “A93” B “A45” A “A94” B “A95” B “A114” B“A96” B “A115” A “A97” B “A116” A “A98” B “A117” A “A99” A “A118” B“A100” A “A119” B “A101” A “A120” A “A102” A “A121” A “A103” A “A122” A“A104” A “A123” B “A105” B “A124” B “A106” A “A125” A “A107” B “A126” B“A108” B “A127” B “A109” A “A128” B “A110” A “A129” A “A111” B “A130” A“A112” B “A131” A “A113” B “A132” A IC₅₀: 1 nM-0.1M = A 0.1M-10M =B >10M = C

The following examples relate to medicaments:

EXAMPLE A Injection Vials

A solution of 100 g of an active compound of the formula I and 5 g ofdisodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH6.5 using 2 N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions. Each injection vial contains 5 mg of activecompound.

EXAMPLE B Suppositories

A mixture of 20 g of an active compound of the formula I with 100 g ofsoya lecithin and 1400 g of cocoa butter is melted, poured into mouldsand allowed to cool. Each suppository contains 20 mg of active compound.

EXAMPLE C Solution

A solution is prepared from 1 g of an active compound of the formula I,9.38 g of NaH₂PO₄·2 H₂O, 28.48 g of Na₂HPO_(4 ·)12H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D Ointment

500 mg of an active compound of the formula I are mixed with 99.5 g ofVaseline under aseptic conditions.

EXAMPLE E Tablets

A mixture of 1 kg of active compound of the formula I, 4 kg of lactose,1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearateis pressed in a conventional manner to give tablets in such a way thateach tablet contains 10 mg of active compound.

EXAMPLE F Dragees

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE G Capsules

2 kg of active compound of the formula I are introduced into hardgelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active compound.

EXAMPLE H Ampoules

A solution of 1 kg of active compound of the formula I in 60 l ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active compound.

The invention claimed is:
 1. A compound, which is one of the followingcompounds A1 1-Methyl-1H-imidazole-4-sulfonic acid[3-(6-methoxybenzo-1,3-dioxo-4-ylamino)quinoxalin-2-yl] amide; A24-Cyano-N{3-[2(3-dimethylaminopropyl)-3,5-dimethoxyphenylaminol]-quinoxalin-2-yl}benzenesulfonamide; A34-Cyano-N-(3-{2-[3-(1,1-dioxo-1-lambda*6*-thiomorpholin-4-yl)propyl]-3,5-dimethoxyphenylamino}quinoxalin-2-yl)benzenesulfonamide;A4 1-Methyl-1H-imidazole-4-sulfonic acid (3-{2-[3-(1,1-dioxo-1-lambda*6*-thiomorpholin-4-yl)propyl]-3,5-dimethoxyphenylamino}quinoxalin-2-yl)amide; A5 1-Methyl-1H-imidazole-4-sulfonicacid[3-(2-hydroxymethyl-5-methoxy-2,3-dihydrobenzofuran-7-ylamino)quinoxalin-2-yl]amide; A64-Cyano-N-{3-[2-(4-hydroxybutyl)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}-benzenesulfonamide;A7 1-Methyl-1H-imidazole-4-sulfonic acid{3-[2-(4-hydroxybutyl)-3,5-dimethoxyphenylamino]quinoxalin-2-yl} amide;A84-[3-(7-Methoxy-2,3-dihydrobenzo-1,4-dioxin-5-ylamino)quinoxalin-2-ylsulfamoyl]-N,N-dimethylbenzamide;A9 5-Methoxy-7-[3-(1-methyl-1H-imidazole-4-sulfonylamino)quinoxalin-2-ylamino]benzofuran-2-carboxylicacid dimethyl amide; A10 1-Methyl-1H-imidazole-4-sulfonic acid[3-(7-methoxy-2,3-dihydrobenzo-1,4-dioxin-5-ylamino)quinoxalin-2-yl]amide; A11 1-Methyl-1H-imidazole-4-sulfonic acid[3-(2,5-dimethoxy-3-methyl-phenylamino)quinoxalin-2-yl] amide; A124-[3-(2,5-Dimethoxy-3-methylphenylamino)quinoxalin-2-ylsulfamoyl]-N,N-dimethylbenzamide;A134-[3-(2-Ethyl-3,5-dimethoxyphenylamino)quinoxalin-2-ylsulfamoyl]-N,N-dimethylbenzamide;A14 1-Methyl-1H-imidazole-4-sulfonic acid[3-(2-ethyl-3,5-dimethoxyphenylamino)-quinoxalin-2-yl] amide; A154-[3-(5-Methoxybenzofuran-7-ylamino)quinoxalin-2-ylsulfamoyl]-N,N-dimethyl-benzamide;A16 1-Methyl-1H-imidazole-4-sulfonic acid[3-(5-methoxybenzofuran-7-ylamino)-quinoxalin-2-yl] amide; A171-Methyl-1H-imidazole-4-sulfonic acid[3-(3-ethyl-2,5-dimethoxyphenylamino)-quinoxalin-2-yl] amide; A184-[3-(3-Ethyl-2,5-dimethoxyphenylamino)quinoxalin-2-ylsulfamoyl]-N,N-dimethylbenzamide;A19 1-Methyl-1H-imidazole-4-sulfonic acid[3-(2-bromo-3,5-dimethoxyphenylamino)quinoxalin-2-yl] amide; A201-Methyl-1H-imidazole-4-sulfonic acid[3-(2-chloro-3,5-dimethoxyphenylamino)quinoxalin-2-yl] amide; A21Pyridine-4-sulfonic acid{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]-quinoxalin-2-yl}amide; A22 Thiazole-5-sulfonic acid{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]-quinoxalin-2-yl}amide; A23 1-(2-Dimethylaminoethyl)-1H-pyrazole-4-sulfonic acid{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}amide; A24 1-Methyl-1H-pyrazole-3-sulfonic acid{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}amide; A25N-{3-[2-(3-Hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}-methanesulfonamide;A26N-{3[2-(3-Hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}-2-methoxybenzenesulfonamide;A27 2 -(4{3-[2-(3-Hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-ylsulfamoyl}pyrazol-1-yl)-N,N-dimethylacetamide;A28 2-Dimethylaminomethyl-1-methyl-1H-imidazole-4-sulfonic acid{3-[2-(3-hydroxybutoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl} amide;A29 1-Difluoromethyl-1H-pyrazole-4-sulfonic acid{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}amide; A30N-{3-[2-(3-Hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}-benzenesulfonamide;A31 2-Dimethylaminomethyl-1-methyl-1H-imidazole-4-sulfonic acid[3-(2,3,5-trimethoxyphenylamino)quinoxalin-2-yl] amide; A321-Methyl-1H-imidazole-4-sulfonic acid{3-[2-(3-hydroxy-2-methylpropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}amide; A33 2-Dimethylaminomethyl-1-methyl-1H-imidazole-4-sulfonic acid{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}amide; A34 Ethyl(4-{3[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-ylsulfamoyl}phenyl)carbamate;A35 1,1-Dioxotetrahydro-1-lambda*6*-thiophene-3-sulfonic acid{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}amide; A36 3-Methanesulfonylpropan-1-sulfonic acid{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}amide; A384-Dimethylaminomethyl-N-{3[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}benzenesulfonamide;A39C,C,C-Trifluoro-N-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]-quinoxalin-2-yl}methanesulfonamide;A40C,C,C-Trifluoro-N-[3-(2,3,5-trimethoxyphenylamino)quinoxalin-2-yl]methanesulfonamide;A41 5-Cyanothiophene-2-sulfonic acid{3-[2-(2-methanesulfonylethoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}amide; A42 1-Methyl-1H-imidazole-4-sulfonic acid{3-[2-(3-hydroxybutoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl} amide;A43 1-Methyl-1H-pyrazole-4-sulfonic acid{3-[2-(3-hydroxybutoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl} amide;A44 1-Methyl-1H-pyrazole-4-sulfonic acid{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}amide; A454-Cyano-N{3-[2-(3-hydroxybutoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}benzenesulfonamide;A462-Cyano-N-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}benzenesulfonamide;A47 1-Methyl-1H-imidazole-4-sulfonic acid(3-{3,5-dimethoxy-2-[2-(2-methoxy-ethoxy)ethoxy]phenylamino}quinoxalin-2-yl)amide; A484-Cyano-N-(3-{3,5-dimethoxy-2-[2-(2-methoxyethoxy)ethoxy]phenylamino}-quinoxalin-2-yl)benzenesulfonamide;A49C,C,C-Trifluoro-N-(3-{2-[2-(2-hydroxyethoxy)ethoxy]-3,5-dimethoxyphenylamino}quinoxalin-2-yl)methanesulfonamide;A50N-(4-{3-[2-(3-Hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-ylsulfamoyl}phenyl)acetamide;A51 5-Cyanothiophene-2-sulfonic acid{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}amide; A52 1-Methyl-1H-imidazole-4-sulfonic acid{3-[2-(2-methanesulfinylethoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}amide; A534-Fluoro-N-(3-{2-[2-(2-hydroxyethoxy)ethoxy]-3,5-dimethoxyphenylamino}-quinoxalin-2-yl)benzenesulfonamide;A54 1-Methyl-1H-imidazole-4-sulfonic acid{3-[3,5-dimethoxy-2-(2-morpholin-4-yl-ethoxy)phenylamino]quinoxalin-2-yl}amide; A55 1-Methyl-1H-imidazole-4-sulfonic acid{3-[2-(2-methanesulfonylethoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}amide; A56 Propane-1-sulfonic acid(3-{2-[2-(2-hydroxyethoxy)ethoxy]-3,5-dimethoxyphenylamino}quinoxalin-2-yl)amide; A574-Dimethylaminomethyl-N-(3-{2-[2-(2-hydroxyethoxy)ethoxy]-3,5-dimethoxyphenylamino}quinoxalin-2-yl)benzenesulfonamide;A58-N-(3-{2-[2-(2-Hydroxyethoxy)ethoxy]-3,5-dimethoxyphenylamino}quinoxalin-2-yl)benzenesulfonamide;A59 5-Cyanothiophene-2-sulfonic acid(3-{2-[2-(2-hydroxyethoxy)ethoxy]-3,5-dimethoxyphenylamino}quinoxalin-2-yl)amide; A60 Thiophene-2-sulfonic acid[3-(2-{2-[(2-hydroxyethyl)methylamino]ethoxy}-3,5-dimethoxyphenylamino)quinoxalin-2-yl]amide; A61N-(3-{2-[2-(2-Hydroxyethoxy)ethoxy]-3,5-dimethoxyphenylamino}quinoxalin-2-yl)-4-methoxybenzenesulfonamide;A62N-[4-(3-{2-[2-(2-Hydroxyethoxy)ethoxy]-3,5-dimethoxyphenylamino}-quinoxalin-2-ylsulfamoyl)phenyll]acetamide;A633-Cyano-N-(3-{2-[2-(2-hydroxyethoxy)ethoxy]-3,5-dimethoxyphenylamino}-quinoxalin-2-yl)benzenesulfonamide;A64 Thiophene-2-sulfonic acid(3-{2-[2-(2-hydroxyethoxy)ethoxy]-3,5-dimethoxy-phenylamino}quinoxalin-2-yl)amide; A65 Pyridine-3-sulfonic acid(3-{2-[2-(2-hydroxyethoxy)ethoxy]-3,5-dimethoxy-phenylamino}quinoxalin-2-yl)amide; A66 Thiophene-2-sulfonic acid{3[2-(2-hydroxyethoxy)-3,5-dimethoxyphenylamino]-quinoxalin-2-yl} amide;A67 Pyridine-3-sulfonic acid(3-{2-[2-(2-hydroxyethanesulfonyl)ethoxy]-3,5-dimethoxyphenylamino}quinoxalin-2-yl)amide; A68 Pyridine-3-sulfonic acid[3-(2-{2-[(2-hydroxyethyl)-methylamino]ethoxy}-3,5-dimethoxyphenylamino)quinoxalin-2-yl]amide; A69 4-(3-{2-[2-(2-Hydroxyethoxy)ethoxy]-3,5-dimethoxyphenylamino}quinoxalin-2-ylsulfamoyl)-N,N-dimethylbenzamide;A704-Cyano-N-{3-[3,5-dimethoxy-2-(2-morpholin-4-ylethoxy)phenylamino]-quinoxalin-2-yl}benzenesulfonamide;A713,4-Difluoro-N-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]-quinoxalin-2-yl}benzenesulfonamide;A724-Cyano-N-(3-{2-[2-(2-hydroxyethanesulfinyl)ethoxy]-3,5-dimethoxyphenylamino}quinoxalin-2-yl)benzenesulfonamide;A733,4-Difluoro-N-(3-{2-[2-(2-hydroxyethoxy)ethoxy]-3,5-dimethoxyphenylamino}-quinoxalin-2-yl)benzenesulfonamide;A744-Cyano-N-{3-[2-(2,3-dihydroxypropoxy)-3,5-dimethoxyphenylamino]-quinoxalin-2-yl}benzenesulfonamide;A75 1-Methyl-1H-imidazole-4-sulfonic acid{3-[2-(2,3-dihydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}amide; A764-Cyano-N-(3-{2-[2-(2-hydroxyethanesulfonyl)ethoxy]-3,5-dimethoxyphenylamino}quinoxalin-2-yl)benzenesulfonamide;A77 1 -Methyl-1H-imidazole-4-sulfonic acid(3-{2-[2-(2-hydroxyethanesulfonyl)-ethoxy]-3,5-dimethoxyphenylamino}quinoxalin-2-yl)amide; A784-Cyano-N-[3-(2-{2-[(2-hydroxyethyl)methylamino]ethoxy}-3,5-dimethoxyphenylamino)quinoxalin-2-yl]benzenesulfonamide;A79 Pyridine-3-sulfonic acid{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]-quinoxalin-2-yl}amide; A804-Cyano-N-(3-{2-[2-(2-hydroxyethoxy)ethoxy]-3,5-dimethoxyphenylamino}-quinoxalin-2-yl)benzenesulfonamide;A81 1-Methyl-1H-imidazole-4-sulfonic acid(3-{2-[2-(2-hydroxyethoxy)ethoxy]-3,5-dimethoxyphenylamino}quinoxalin-2-yl)amide; A824-Cyano-N-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}benzenesulfonamide;A83 1-Methyl-1H-imidazole-4-sulfonic acid[3-(5-difluoromethoxy-2,3-dimethoxyphenylamino)quinoxalin-2-yl] amide;A844-Cyano-N-[3-(5-difluoromethoxy-2,3-dimethoxyphenylamino)quinoxalin-2-yl]-benzenesulfonamide;A854-[3-(5-Difluoromethoxy-2,3-dimethoxyphenylamino)quinoxalin-2-ylsulfamoyl]-N,N-dimethylbenzamide;A86 1-Methyl-1H-imidazole-4-sulfonic acid{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}amide; A874-{3-[2-(3-Hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-ylsulfamoyl}-N,N-dimethylbenzamide;A884-{3-[2-(2-Hydroxyethoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-ylsulfamoyl}-N,N-dimethylbenzamide;A89 1-Methyl-1H-imidazole-4-sulfonic acid{3-[2-(2-hydroxyethoxy)-3,5-dimethoxy-phenylamino]quinoxalin-2-yl}amide; A90N,N-Dimethyl-4-[3-(2,3,5-trimethoxyphenylamino)quinoxalin-2-ylsulfamoyl]-benzamide;A914-Cyano-N-[3-(2,3,5-trimethoxyphenylamino)quinoxalin-2-yl]-benzenesulfonamide;A92 1-Methyl-1H-imidazole-4-sulfonic acid[3-(2,3,5-trimethoxyphenylamino)-quinoxalin-2-yl] amide; A93N-{3-[2-(3-Hydroxybutoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}-methanesulfonamide;A94 2-Dimethylaminomethyl-1-methyl-1H-imidazole-4-sulfonic acid{3-[2-(4-hydroxybutyl)-3,5-dimethoxyphenylamino]quinoxalin-2-yl} amide;A954-{3-[2-(3-Hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-ylsulfamoyl}-N-(2,2,2-trifluoroethyl)benzamide;A96 2-Cyanoethanesulfonic acid{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}amide; A973-{3-[2-(3-Hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-ylsulfamoyl}-N,N-dimethylbenzamide;A984-(3,3-Difluoroazetidine-1-carbonyl)-N-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}benzenesulfonamide;A99N-{3-[2-(3-Hydroxybutoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}methanesulfonamide;A100 1-Methyl-1H-pyrazole-3-sulfonic acid{3-[2-(3-hydroxybutoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl} amide;A101 Thiazole-5-sulfonic acid{3-[2-(3-hydroxybutoxy)-3,5-dimethoxyphenylamino]-quinoxalin-2-yl}amide; A1024-(Azetidine-1-carbonyl)-N-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}benzenesulfonamide;A103 1-Difluoromethyl-1H-pyrazole-4-sulfonic acid{3-[2-(3-hydroxybutoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl} amide;A 104

A1053-{3-[2-(3-Hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-ylsulfamoyl}-N-(2,2,2-trifluoroethyl)benzamide;A1064-Aminomethyl-N-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]-quinoxalin-2-yl}benzenesulfonamide;A1073-(3,3-Difluoroazetidine-1-carbonyl)-N-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}benzenesulfonamide;A1083-(Azetidine-1-carbonyl)-N-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}benzenesulfonamide;A1093-Dimethylaminomethyl-N-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}benzenesulfonamide;A1104-(3,3-Difluoroazetidin-1-ylmethyl)-N-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}benzenesulfonamide;A1114-Azetidin-1-ylmethyl-N-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}benzenesulfonamide;A112 1-Methyl-1H-pyrazole-3-sulfonic acid(3-{2-[2-(2-hydroxyethoxy)ethoxy]-3,5-dimethoxyphenylamino}quinoxalin-2-yl)amide; A113 2-Dimethylaminomethyl-1-methyl-1H-imidazole-4-sulfonic acid{3-[2(4-hydroxybutoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl} amide;A114C,C-Difluoro-N-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]-quinoxalin-2-yl}methanesulfonamide;A115C,C-Difluoro-N-{3-[2-(3-hydroxybutoxy)-3,5-dimethoxyphenylamino]-quinoxalin-2-yl}-methanesulfonamide;A1163-Azetidin-1-ylmethyl-N-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}benzenesulfonamide;A117 1-Methyl-1H-pyrazole-3-sulfonic acid{3-[2-(4-hydroxybutyl)-3,5-dimethoxyphenylamino]quinoxalin-2-yl} amide;A1182,2-Difluoro-2-(3-{3-[2-(3-hydroxybutoxy)-3,5-dimethoxyphenylamino]-quinoxalin-2-ylsulfamoyl}pyrazol-1-yl)-N,N-dimethylacetamide;A1192,2-Difluoro-2-(3-{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]-quinoxalin-2-ylsulfamoyl}pyrazol-1-yl)-N,N-dimethylacetamide;A1202-(3-{3-[2-(3-Hydroxybutoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-ylsulfamoyl}pyrazol-1-yl)-N,N-dimethylacetamide;A121 1-Methyl-1H-pyrazole-3-sulfonic acid[3-(2,3,5-trimethoxyphenylamino)-quinoxalin-2-yl] amide; A1222-(3-{3-[2-(3-Hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-ylsulfamoyl}pyrazol-1-yl)-N,N-dimethylacetamide;A123 2-Diethylaminomethyl-1-methyl-1H-imidazole-4-sulfonic acid{3-[2-(3-hydroxy-butoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}amide; A124 1-Methyl-1H-imidazole-4-sulfonic acid[3-(2-hydroxymethyl-7-methoxy-2,3-dihydrobenzo-1,4-dioxin-5-ylamino)quinoxalin-2-yl]amide; A125 1-Methyl-1H-pyrazole-3-sulfonic acid{3-[2-(3-hydroxy-3-methylbutoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}amide; A126 2-Diethylaminomethyl-1-methyl-1H-imidazole-4-sulfonic acid{3-[2-(3-hydroxy-propoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}amide; A127 1-Methyl-1H-imidazole-4-sulfonic acid[3-(3-hydroxymethyl-7-methoxy-2,3-dihydrobenzo-1,4-dioxin-5-ylamino)quinoxalin-2-yl]amide; A128 2-Dimethylaminomethyl-1-methyl-1H-imidazole-4-sulfonic acid{3-[2(3-hydroxy-3-methylbutoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}amide; A129 1-(2-Dimethylaminoethyl)-1H-pyrazole-3-sulfonic acid{3-[2-(3-hydroxybutoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl} amide;A130 1-(2-Dimethylaminoethyl)-1H-pyrazole-3-sulfonic acid{3-[2-(3-hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-yl}amide; A131N,N-Dimethyl-2-{3-[3-(2,3,5-trimethoxyphenylamino)quinoxalin-2-ylsulfamoyl]-pyrazol-1-yl}acetamide;or A132N-(4-{3-[2-(3-Hydroxypropoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-ylsulfamoyl}benzyl)acetamide;or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.2. The compound according to claim 1, which is a compound selected fromthe group consisting of compounds A1, A2, A3, A4, A5, A6, A7, A8, A9,A10, A 11, A12, A13, A14, A15 and A16 or is a pharmaceuticallyacceptable salt, tautomer or stereoisomer thereof.
 3. The compoundaccording to claim 1, which is a compound selected from the groupconsisting of compounds A17, A18, A19, A20, A21, A22, A23, A24, A25,A26, A27, A28, A29, A30, A31, A32 and A33 or is a pharmaceuticallyacceptable salt, tautomer or stereoisomer thereof.
 4. The compoundaccording to claim 1, which is a compound selected from the groupconsisting of compounds A34, A35, A36, A38, A39, A40, A41, A42, A43,A44, A45, A46, A47, A48, A49 and A50 or is a pharmaceutically acceptablesalt, tautomer or stereoisomer thereof.
 5. The compound according toclaim 1, which is a compound selected from the group consisting ofcompounds A51, A52, A53, A54, A55, A56, A57, A58, A59, A60, A61, A62,A63, A64, A65, A66 and A67 or is a pharmaceutically acceptable salt,tautomer or stereoisomer thereof.
 6. The compound according to claim 1,which is a compound selected from the group consisting of compounds A68,A69, A70, A71, A72, A73, A74, A75, A76, A77, A78, A79, A80, A81, A82,A83, A84 and A85 or is a pharmaceutically acceptable salt, tautomer orstereoisomer thereof.
 7. The compound according to claim 1, which is acompound selected from the group consisting of compounds A86, A87, A88,A89, A90, A91, A92, A93, A94, A95, A96, A97, A98, A99, A100 and A101 oris a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.8. The compound according to claim 1, which is a compound selected fromthe group consisting of compounds A102, A103, A104, A105, A106, A107,A108, A109, A110, A111, A112, A113, A114, A115 and A116 or is apharmaceutically acceptable salt, tautomer or stereoisomer thereof. 9.The compound according to claim 1, which is a compound selected from thegroup consisting of compounds A117, A118, A119, A120, A121, A122, A123,A124, A125, A126, A127, A128, A129, A130, A131 and A132 or is apharmaceutically acceptable salt, tautomer or stereoisomer thereof. 10.A pharmaceutical composition comprising a compound of claim 2 or apharmaceutically acceptable salt, tautomer or stereoisomer thereof andone or more excipients and/or adjuvants.
 11. A pharmaceuticalcomposition comprising a compound of claim 3 or a pharmaceuticallyacceptable salt, tautomer or stereoisomer thereof and one or moreexcipients and/or adjuvants.
 12. A pharmaceutical composition comprisinga compound of claim 4 or a pharmaceutically acceptable salt, tautomer orstereoisomer thereof and one or more excipients and/or adjuvants.
 13. Apharmaceutical composition comprising a compound of claim 5 or apharmaceutically acceptable salt, tautomer or stereoisomer thereof andone or more excipients and/or adjuvants.
 14. A pharmaceuticalcomposition comprising a compound of claim 6 or a pharmaceuticallyacceptable salt, tautomer or stereoisomer thereof and one or moreexcipients and/or adjuvants.
 15. A pharmaceutical composition comprisinga compound of claim 7 or a pharmaceutically acceptable salt, tautomer orstereoisomer thereof and one or more excipients and/or adjuvants.
 16. Apharmaceutical composition comprising a compound of claim 8 or apharmaceutically acceptable salt, tautomer or stereoisomer thereof andone or more excipients and/or adjuvants.
 17. A pharmaceuticalcomposition comprising a compound of claim 9 or a pharmaceuticallyacceptable salt, tautomer or stereoisomer thereof and one or moreexcipients and/or adjuvants.
 18. A pharmaceutical composition comprisinga compound of claim 1 or a pharmaceutically acceptable salt, tautomer orstereoisomer thereof and one or more excipients and/or adjuvants.
 19. Akit comprising separate packs of (a) a compound of claim 1 or apharmaceutically acceptable salt, tautomer or stereoisomer thereof, and(b) a further pharmaceutically active compound.